C6-azaspiro iminothiadiazine dioxides as bace inhibitors, compositions, and their use

ABSTRACT

In its many embodiments, the present invention provides certain C2-ring-substituted thiadiazine compounds, including compounds Formula (I): (structure represented) or tautomers thereof, and pharmaceutically acceptable salts of said compounds and said tautomers, wherein R 1 , R 4 , ring A, R A , m, -L 1 -, R L , and ring C are as defined herein. The novel compounds of the invention are useful as BACE inhibitors and/or for the treatment and prevention of various pathologies related thereto. Pharmaceutical compositions comprising one or more such compounds (alone and in combination with one or more other active agents), and methods for their preparation and use, including for the possible treatment of Alzheimer&#39;s disease, are also disclosed.

FIELD OF THE INVENTION

This invention provides certain C6-azaspiro iminothiadiazine dioxidecompounds, and compositions comprising these compounds, as inhibitors ofBACE, which may be useful for treating or preventing pathologies relatedthereto.

BACKGROUND

Amyloid beta peptide (“Aβ”) is a primary component of β amyloid fibrilsand plaques, which are regarded as having a role in an increasing numberof pathologies. Examples of such pathologies include, but are notlimited to, Alzheimer's disease, Down's syndrome, Parkinson's disease,memory loss (including memory loss associated with Alzheimer's diseaseand Parkinson's disease), attention deficit symptoms (includingattention deficit symptoms associated with Alzheimer's disease (“AD”),Parkinson's disease, and Down's syndrome), dementia (includingpre-senile dementia, senile dementia, dementia associated withAlzheimer's disease, Parkinson's disease, and Down's syndrome),progressive supranuclear palsy, cortical basal degeneration,neurodegeneration, olfactory impairment (including olfactory impairmentassociated with Alzheimer's disease, Parkinson's disease, and Down'ssyndrome), β-amyloid angiopathy (including cerebral amyloid angiopathy),hereditary cerebral hemorrhage, mild cognitive impairment (“MCI”),glaucoma, amyloidosis, type II diabetes, hemodialysis (β2 microglobulinsand complications arising therefrom), neurodegenerative diseases such asscrapie, bovine spongiform encephalitis, Creutzfeld-Jakob disease,traumatic brain injury and the like.

Aβ peptides are short peptides which are made from the proteolyticbreak-down of the transmembrane protein called amyloid precursor protein(“APP”). Aβ peptides are made from the cleavage of APP by β-secretaseactivity at a position near the N-terminus of Aβ, and by gamma-secretaseactivity at a position near the C-terminus of Aβ. (APP is also cleavedby α-secretase activity, resulting in the secreted, non-amyloidogenicfragment known as soluble APPα.) Beta site APP Cleaving Enzyme(“BACE-1”) is regarded as the primary aspartyl protease responsible forthe production of Aβ by β-secretase activity. The inhibition of BACE-1has been shown to inhibit the production of Aβ.

AD is estimated to afflict more than 20 million people worldwide and isbelieved to be the most common cause of dementia. AD is a diseasecharacterized by degeneration and loss of neurons and also by theformation of senile plaques and neurofibrillary tangles. Presently,treatment of Alzheimer's disease is limited to the treatment of itssymptoms rather than the underlying causes. Symptom-improving agentsapproved for this purpose include, for example, N-methyl-D-aspartatereceptor antagonists such as memantine (Namenda®, ForestPharmaceuticals, Inc.), cholinesterase inhibitors such as donepezil(Aricept®, Pfizer), rivastigmine (Exelon®, Novartis), galantamine(Razadyne Reminyl®), and tacrine (Cognex®).

In AD, Aβ peptides, formed through β-secretase and gamma-secretaseactivity, can form tertiary structures that aggregate to form amyloidfibrils. Aβ peptides have also been shown to form Aβ oligomers(sometimes referred to as “Aβ aggregates” or “Abeta oligomers”). Aβoligomers are small multimeric structures composed of 2 to 12 Aβpeptides that are structurally distinct from Aβ fibrils. Amyloid fibrilscan deposit outside neurons in dense formations known as senile plaques,neuritic plaques, or diffuse plaques in regions of the brain importantto memory and cognition. Aβ oligomers are cytotoxic when injected in thebrains of rats or in cell culture. This Aβ plaque formation anddeposition and/or Aβ oligomer formation, and the resultant neuronaldeath and cognitive impairment, are among the hallmarks of ADpathophysiology. Other hallmarks of AD pathophysiology includeintracellular neurofibrillary tangles comprised of abnormallyphosphorylated tau protein, and neuroinflammation.

Evidence suggests that Aβ, Aβ fibrils, aggregates, oligomers, and/orplaque play a causal role in AD pathophysiology. (Ohno et al.,Neurobiology of Disease, No. 26 (2007), 134-145). Mutations in the genesfor APP and presenilins 1/2 (PS1/2) are known to cause familial AD andan increase in the production of the 42-amino acid form of Aβ isregarded as causative. Aβ has been shown to be neurotoxic in culture andin vivo. For example, when injected into the brains of aged primates,fibrillar Aβ causes neuronal cell death around the injection site. Otherdirect and circumstantial evidence of the role of Aβ in Alzheimeretiology has also been published.

BACE-1 has become an accepted therapeutic target for the treatment ofAlzheimer's disease. For example, McConlogue et al., J. Bio. Chem., Vol.282, No. 36 (September 2007), have shown that partial reductions ofBACE-1 enzyme activity and concomitant reductions of Aβ levels lead to adramatic inhibition of Aβ-driven AD-like pathology, making β-secretase atarget for therapeutic intervention in AD. Ohno et al. Neurobiology ofDisease, No. 26 (2007), 134-145, report that genetic deletion of BACE-1in 5XFAD mice abrogates Aβ generation, blocks amyloid deposition,prevents neuron loss found in the cerebral cortex and subiculum (brainregions manifesting the most severe amyloidosis in 5XFAD mice), andrescues memory deficits in 5XFAD mice. The group also reports that Aβ isultimately responsible for neuron death in AD and concludes that BACE-1inhibition has been validated as an approach for the treatment of AD.Roberds et al., Human Mol. Genetics, 2001, Vol. 10, No. 12, 1317-1324,established that inhibition or loss of β-secretase activity produces noprofound phenotypic defects while inducing a concomitant reduction inAβ. Luo et al., Nature Neuroscience, Vol. 4, No. 3, March 2001, reportthat mice deficient in BACE-1 have normal phenotype and abolishedβ-amyloid generation.

More recently, Jonsson, et al. have reported in Nature, Vol. 488, pp.96-99 (August 2012), that a coding mutation (A673T) in the APP geneprotects against Alzheimer's disease and cognitive decline in theelderly without Alzheimer's disease. More specifically, the A allele ofrs63750847, a single nucleotide polymorphism (SNP), results in analanine to threonine substitution at position 673 in APP (A673T). ThisSNP was found to be significantly more common in a healthy elderlycontrol group than in an Alzheimer's disease group. The A673Tsubstitution is adjacent to the aspartyl protease beta-site in APP, andresults in an approximately 40% reduction in the formation ofamyloidogenic peptides in a heterologous cell expression system invitro. Jonsson, et al. report that an APP-derived peptide substratecontaining the A673T mutation is processed 50% less efficiently bypurified human BACE1 enzyme when compared to a wild-type peptide.Jonsson et al. indicate that the strong protective effect of theAPP-A673T substitution against Alzheimer's disease provides proof ofprinciple for the hypothesis that reducing the beta-cleavage of APP mayprotect against the disease.

BACE-1 has also been identified or implicated as a therapeutic targetfor a number of other diverse pathologies in which Aβ or Aβ fragmentshave been identified to play a causative role. One such example is inthe treatment of AD-type symptoms of patients with Down's syndrome. Thegene encoding APP is found on chromosome 21, which is also thechromosome found as an extra copy in Down's syndrome. Down's syndromepatients tend to acquire AD at an early age, with almost all those over40 years of age showing Alzheimer's-type pathology. This is thought tobe due to the extra copy of the APP gene found in these patients, whichleads to overexpression of APP and therefore to increased levels of Aβcausing the prevalence of AD seen in this population. Furthermore,Down's patients who have a duplication of a small region of chromosome21 that does not include the APP gene do not develop AD pathology. Thus,it is thought that inhibitors of BACE-1 could be useful in reducingAlzheimer's type pathology in Down's syndrome patients.

Another example is in the treatment of glaucoma (Guo et al., PNAS, Vol.104, No. 33, Aug. 14, 2007). Glaucoma is a retinal disease of the eyeand a major cause of irreversible blindness worldwide. Guo et al. reportthat Aβ colocalizes with apoptotic retinal ganglion cells (RGCs) inexperimental glaucoma and induces significant RGC cell loss in vivo in adose- and time-dependent manner. The group report having demonstratedthat targeting different components of the Aβ formation and aggregationpathway, including inhibition of β-secretase alone and together withother approaches, can effectively reduce glaucomatous RGC apoptosis invivo. Thus, the reduction of Aβ production by the inhibition of BACE-1could be useful, alone or in combination with other approaches, for thetreatment of glaucoma.

Another example is in the treatment of olfactory impairment. Getchell etal., Neurobiology of Aging, 24 (2003), 663-673, have observed that theolfactory epithelium, a neuroepithelium that lines the posterior-dorsalregion of the nasal cavity, exhibits many of the same pathologicalchanges found in the brains of AD patients, including deposits of Aβ,the presence of hyperphosphorylated tau protein, and dystrophic neuritesamong others. Other evidence in this connection has been reported byBacon A W, et al., Ann NY Acad Sci 2002; 855:723-31; Crino P B, Martin JA, Hill W D, et al., Ann Otol Rhinol Laryngol, 1995; 104:655-61; DaviesD C, et al., Neurobiol Aging, 1993; 14:353-7; Devanand D P, et al., Am JPsychiatr, 2000; 157:1399-405; and Doty R L, et al., Brain Res Bull,1987; 18:597-600. It is reasonable to suggest that addressing suchchanges by reduction of Aβ by inhibition of BACE-1 could help to restoreolfactory sensitivity in patients with AD.

For compounds which are inhibitors of BACE-2, another example is in thetreatment of type-II diabetes, including diabetes associated withamyloidogenesis. BACE-2 is expressed in the pancreas. BACE-2immunoreactivity has been reported in secretory granules of beta cells,co-stored with insulin and IAPP, but lacking in the other endocrine andexocrine cell types. Stoffel et al., WO2010/063718, disclose the use ofBACE-2 inhibitors in the treatment of metabolic diseases such as Type-IIdiabetes. The presence of BACE-2 in secretory granules of beta cellssuggests that it may play a role in diabetes-associated amyloidogenesis.(Finzi, G. Franzi, et al., Ultrastruct Pathol. 2008 November-December;32(6):246-51.)

Other diverse pathologies characterized by the formation and depositionof Aβ or fragments thereof, and/or by the presence of amyloid fibrils,oligomers, and/or plaques, include neurodegenerative diseases such asscrapie, bovine spongiform encephalitis, traumatic brain injury (“TBI”),Creutzfeld-Jakob disease and the like, type II diabetes (which ischaracterized by the localized accumulation of cytotoxic amyloid fibrilsin the insulin producing cells of the pancreas), and amyloid angiopathy.In this regard reference can be made to the patent literature. Forexample, Kong et al., US2008/0015180, disclose methods and compositionsfor treating amyloidosis with agents that inhibit Aβ peptide formation.As another example, Loane, et al. report the targeting of amyloidprecursor protein secretases as therapeutic targets for traumatic braininjury. (Loane et al., “Amyloid precursor protein secretases astherapeutic targets for traumatic brain injury”, Nature Medicine,Advance Online Publication, published online Mar. 15, 2009.) Still otherdiverse pathologies characterized by the inappropriate formation anddeposition of Aβ or fragments thereof, and/or by the presence of amyloidfibrils, and/or for which inhibitor(s) of BACE-1 is expected to be oftherapeutic value are discussed further hereinbelow.

SUMMARY OF THE INVENTION

The present invention provides certain C6-azaspiro thiadiazine dioxidecompounds, which are collectively or individually referred to herein as“compound(s) of the invention”, as described herein. The compounds ofthe invention are useful as inhibitors of BACE-1 and/or BACE-2.

In one embodiment, the compounds of the invention have the structuralFormula (I):

or a tautomer thereof having the structural Formula (I′):

and pharmaceutically acceptable salts thereof, wherein:

R¹ is selected from the group consisting of H, alkyl, heteroalkyl,cycloalkyl, and -alkyl-cycloalkyl, wherein each said alkyl, heteroalkyl,cycloalkyl, and -alkyl-cycloalkyl is optionally substituted with one ormore halogen;

ring C is a moiety selected from the group consisting of

each R² is independently selected from the group consisting of H,-alkyl-OH, alkyl, heteroalkyl, and cycloalkyl wherein each said alkyl,heteroalkyl, and cycloalkyl of R² is optionally substituted withhalogen;

each R³ is independently selected from the group consisting of H,halogen, -alkyl-OH, alkyl, heteroalkyl, alkoxy, and cycloalkyl, whereineach said alkyl, heteroalkyl, alkoxy, and cycloalkyl of R³ is optionallysubstituted with halogen;

R^(N) is selected from the group consisting of: H, —C(O)R^(6N),—C(O)OR^(6N), —C(O)N(R^(6N))₂, —S(O)₂R^(6N), —S(O)₂N(R^(6N))₂, alkyl,heteroalkyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl,-alkyl-heterocycloalkyl, aryl, -alkyl-aryl, heteroaryl, and-alkyl-heteroaryl,

-   -   wherein said alkyl, heteroalkyl, cycloalkyl, -alkyl-cycloalkyl,        heterocycloalkyl, -alkyl-heterocycloalkyl, aryl, -alkyl-aryl,        heteroaryl, and -alkyl-heteroaryl, of R^(N) are each optionally        independently unsubstituted or substituted with one or more        groups independently selected from R⁹;

R⁴ is selected from the group consisting of H, alkyl, heteroalkyl,cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and-alkyl-heterocycloalkyl, wherein each said alkyl, heteroalkyl,cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and-alkyl-heterocycloalkyl is optionally substituted with one or morehalogen;

ring A is selected from the group consisting of aryl and heteroaryl;

m is 0 or more;

each R^(A) (when present) is independently selected from the groupconsisting of: halogen, oxo, —OH, —CN, —SF₅, —OSF₅, —Si(R^(5A))₃,—N(R^(6A))₂, —OR^(6A), —SR^(6A), alkyl, heteroalkyl, alkenyl, alkynyl,cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and-alkyl-heterocycloalkyl,

-   -   wherein said alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,        -alkyl-cycloalkyl, heterocycloalkyl, and -alkyl-heterocycloalkyl        of R^(A) are each optionally independently unsubstituted or        substituted with one or more groups independently selected from        R⁸;

-L₁- is a divalent moiety selected from the group consisting of —NHC(O)—and —C(O)NH—;

R^(L) is selected from the group consisting of alkyl and heteroalkyl,wherein said alkyl and heteroalkyl of R^(L) are each optionallyunsubstituted or substituted with one or more halogen;

or, alternatively, R^(L) is a moiety having the formula

wherein q is 0 or 1;

-L_(B)- (when present) is a divalent moiety selected from the groupconsisting of lower alkyl and lower heteroalkyl, wherein each said loweralkyl and lower heteroalkyl is optionally substituted with one or morehalogen;

ring B is selected from the group consisting of aryl, heteroaryl,cycloalkyl, cycloalkenyl, heterocycloalkyl, and heterocycloalkenyl;

p is 0 or more; and

each R^(B) (when present) is independently selected from the groupconsisting of: halogen, oxo, —OH, —CN, —SF₅, —OSF₅, —Si(R^(5B))₃,—N(R^(6B))₂, —NR^(7B)C(O)R^(6B), —NR^(7B)S(O)₂R^(6B),—NR^(7B)S(O)₂N(R^(6B))₂, —NR^(7B)C(O)N(R^(6B))₂, —NR^(7B)C(O)OR^(6B),—C(O)R^(6B), —C(O)OR^(6B), —C(O)N(R^(6B))₂, —S(O)R^(6B), —S(O)₂R^(6B),—S(O)₂N(R^(6B))₂, —OR^(6B), —SR^(6B), alkyl, heteroalkyl, alkenyl,alkynyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl,-alkyl-heterocycloalkyl, aryl, -alkyl-aryl, heteroaryl, and-alkyl-heteroaryl.

-   -   wherein said alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,        -alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkyl,        aryl, -alkyl-aryl, heteroaryl, and -alkyl-heteroaryl, of R^(B)        are each optionally independently unsubstituted or substituted        with one or more groups independently selected from R⁹;

each R^(5A) and R^(5B) (when present) is independently selected from thegroup consisting of alkyl, heteroalkyl, cycloalkyl, -alkyl-cycloalkyl,heterocycloalkyl, -alkyl-heterocycloalkyl,

-   -   wherein each said alkyl, heteroalkyl, cycloalkyl,        -alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkyl of        R^(5A) and R^(5B) is unsubstituted or substituted with one or        more halogen;

each R^(6N) and R^(6A) (when present) is independently selected from thegroup consisting of H, alkyl, -alkyl-OH, alkenyl, alkynyl, heteroalkyl,-heteroalkyl-OH, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl,-alkyl-heterocycloalkyl, aryl, heteroaryl, -alkyl-aryl, and-alkyl-heteroaryl,

wherein each said alkyl, -alkyl-OH, alkenyl, alkynyl, heteroalkyl,-heteroalkyl-OH, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl,-alkyl-heterocycloalkyl, aryl, -alkyl-aryl, heteroaryl, and-alkyl-heteroaryl of R^(6N) and R^(6A) is unsubstituted or substitutedwith one or more groups independently selected from halogen, alkyl,cycloalkyl, heteroalkyl, haloalkyl, alkoxy, heteroalkoxy, andhaloalkoxy;

each R^(6B) (when present) is independently selected from the groupconsisting of H, alkyl, -alkyl-OH, alkenyl, alkynyl, heteroalkyl,-heteroalkyl-OH, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl,-alkyl-heterocycloalkyl, aryl, -alkyl-aryl, heteroaryl, and-alkyl-heteroaryl,

-   -   wherein each said alkyl, -alkyl-OH, alkenyl, alkynyl,        heteroalkyl, -heteroalkyl-OH, cycloalkyl, -alkyl-cycloalkyl,        heterocycloalkyl, -alkyl-heterocycloalkyl, aryl, -alkyl-aryl,        heteroaryl, and -alkyl-heteroaryl of R^(6B) is unsubstituted or        substituted with one or more groups independently selected from        halogen, alkyl, cycloalkyl, heteroalkyl, haloalkyl, alkoxy,        heteroalkoxy, and haloalkoxy;

each R^(7B) (when present) is independently selected from the groupconsisting of H, alkyl, heteroalkyl, cycloalkyl, -alkyl-cycloalkyl,heterocycloalkyl, and -alkyl-heterocycloalkyl,

-   -   wherein each said alkyl, heteroalkyl, -heteroalkyl-OH,        cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and        -alkyl-heterocycloalkyl of R^(7B) is unsubstituted or        substituted with one or more halogen;

each R⁸ (when present) is independently selected from the groupconsisting of halogen, lower alkyl, lower heteroalkyl, lower alkoxy,lower cycloalkyl, and lower heterocycloalkyl, wherein each said loweralkyl, lower heteroalkyl, lower alkoxy, lower cycloalkyl, and lowerheterocycloalkyl of R⁸ is optionally substituted with halogen; and

each R⁹ (when present) is independently selected from the groupconsisting of halogen, —OH, —CN, —SF₅, —OSF₅, alkyl, -alkyl-OH,heteroalkyl, -heteroalkyl-OH, alkoxy, —O-heteroalkyl, cycloalkyl,-alkyl-cycloalkyl, —O-cycloalkyl, —O-alkyl-cycloalkyl,-heterocycloalkyl, -alkyl-heterocycloalkyl, —O-heterocycloalkyl and—O-alkyl-heterocycloalkyl, wherein each said alkyl, -alkyl-OH,heteroalkyl, -heteroalkyl-OH, alkoxy, —O-heteroalkyl, cycloalkyl,-alkyl-cycloalkyl, —O-cycloalkyl, —O-alkyl-cycloalkyl,-heterocycloalkyl, -alkyl-heterocycloalkyl, —O-heterocycloalkyl and—O-alkyl-heterocycloalkyl are optionally substituted with one or morehalogen.

In other embodiments, the invention provides compositions, includingpharmaceutical compositions, comprising one or more compounds of theinvention (e.g., one compound of the invention), or a tautomer thereof,or a pharmaceutically acceptable salt or solvate of said compound(s)and/or said tautomer(s), optionally together with one or more additionaltherapeutic agents, optionally in an acceptable (e.g., pharmaceuticallyacceptable) carrier or diluent.

In other embodiments, the invention provides various methods oftreating, preventing, ameliorating, and/or delaying the onset of an Aβpathology and/or a symptom or symptoms thereof, comprising administeringa composition comprising an effective amount of one or more compounds ofthe invention, or a tautomer thereof, or pharmaceutically acceptablesalt or solvate of said compound(s) and/or said tautomer(s), to apatient in need thereof. Such methods optionally additionally compriseadministering an effective amount of one or more additional therapeuticagents suitable for treating the patient being treated.

These and other embodiments of the invention, which are described indetail below or will become readily apparent to those of ordinary skillin the art, are included within the scope of the invention.

DETAILED DESCRIPTION

For each of the following embodiments, any variable not explicitlydefined in the embodiment is as defined in Formula (I) or (IA). In eachof the embodiments described herein, each variable is selectedindependently of the other unless otherwise noted.

In one embodiment, the compounds of the invention have the structuralFormula (IA):

or a tautomer thereof having the structural Formula (IA′):

or pharmaceutically acceptable salt thereof, wherein each variable is asdescribed in Formula (I).

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

R¹ is selected from the group consisting of H, methyl, ethyl,cyclopropyl, —CH₂-cyclopropyl, and —CH₂OCH₃.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

R¹ is selected from the group consisting of H and methyl.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

R¹ is methyl.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

each R² is independently selected from the group consisting of H,methyl, ethyl, propyl, —CH₂OH, —CH₂CH₂OH, —CH₂OCH₃, —CH₂OCH₂CH₃,cyclopropyl, —CF₃, —CHF₂, and —CH₂F.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

each R² is independently selected from the group consisting of H,methyl, ethyl, —CH₂OH, —CH₂OCH₃, cyclopropyl, —CF₃, —CHF₂, and —CH₂F.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

each R² is independently selected from the group consisting of H,methyl, —CH₂OH, —CF₃, —CHF₂, and —CH₂F.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

each R² is H.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

each R³ is independently selected from the group consisting of H,fluoro, chloro, methyl, ethyl, propyl, —CH₂OH, —CH₂CH₂OH, —CH₂OCH₃,—CH₂OCH₂CH₃, —OCH₃, —OCH₂CH₃, cyclopropyl, —CF₃, —CHF₂, —CH₂F, —OCF₃,—OCH₂CF₃, —OCHF₂, —OCH₂F, —OCH₂CH₂F.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

each R³ is independently selected from the group consisting of H,fluoro, methyl, ethyl, —CH₂OH, —CH₂OCH₃, —OCH₃, cyclopropyl, —CF₃,—CHF₂, —CH₂F, —OCHF₂, and —OCH₂F.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

each R³ is independently selected from the group consisting of H,methyl, —CH₂OH, —CF₃, —CHF₂, and —CH₂F.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

each R³ is H.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

R^(N) is as defined above; and

each R^(6N) is independently selected from the group consisting of H,lower alkyl, lower heteroalkyl, lower cycloalkyl, -(loweralkyl)-(lowercycloalkyl), lower heterocycloalkyl, -(lower alkyl)-(lowerheterocycloalkyl), aryl, heteroaryl, -(lower alkyl)-aryl, and -(loweralkyl)-heteroaryl,

wherein each said lower alkyl, lower heteroalkyl, lower cycloalkyl,-(lower alkyl)-(lowercycloalkyl), lower heterocycloalkyl, -(loweralkyl)-(lower heterocycloalkyl), aryl, heteroaryl, -(lower alkyl)-aryl,and -(lower alkyl)-heteroaryl of R^(6N) is unsubstituted or substitutedwith one or more groups independently selected from halogen, loweralkyl, lower cycloalkyl, lower heteroalkyl, lower haloalkyl, loweralkoxy, lower heteroalkoxy, and lower haloalkoxy;

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

each R^(N) group is selected from the group consisting of H, —C(O)CH₃,—C(O)CH₂CH₃, —C(O)CH₂CH(CH₃)₂, —C(O)-cyclopropyl, —C(O)—CH₂-cyclopropyl,—C(O)N(CH₃)₂, —C(O)NHCH₃, —S(O)₂CH₃, —S(O)₂CH₂CH₃, —S(O)₂CH₂CF₃,—S(O)₂CH₂CH(CH₃)₂, —S(O)₂-phenyl, —S(O)₂CH₂-pyridyl, —S(O)₂-cyclopentyl,—S(O)₂-cyclopropyl, —S(O)₂-imidazolyl, —S(O)₂—CH₂-tetrahydrofuranyl,—S(O)₂-pyrazolyl, —S(O)₂N(CH₃)₂, —S(O)₂NHCH₃, methyl, ethyl, propyl,cyclopropyl, butyl, —CH₂-cyclopropyl, benzyl, —CH₂OCH₃, —CH₂OCH₂CH₃,phenyl, pyridyl, pyrimidinyl, pyrazinyl, oxadiazolyl, isoxazolyl,oxazolyl, and pyrrolyl, —CH₂-thiazolyl, —CH₂-oxazoyl, —CH₂-pyridyl,—CH₂-pyrimidinyl, —CH₂-pyrazinyl, —CH₂-pyrazolyl, —CH₂-cyclobutyl,—CH₂-cyclopropyl, —CH₂-tetrahydrofuranyl,

wherein said methyl, ethyl, propyl, butyl, —CH₂-cyclopropyl, benzyl,cyclobutyl, cyclopropyl, phenyl, pyridyl, oxadiazolyl, imidazolyl,isoxazolyl, oxazolyl, and pyrrolyl are each optionally unsubstituted orsubstituted with fluorine, chlorine, methyl, —CN, —CF₃, CHF₂, and —OMe.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

each R^(N) group is selected from the group consisting of H, —C(O)CH₃,—C(O)CH₂CH(CH₃)₂, —C(O)-cyclopropyl, —C(O)—CH₂-cyclopropyl, —S(O)₂CH₃,—S(O)₂CH₂CH₃, —S(O)₂CH₂CF₃, —S(O)₂CH₂CH(CH₃)₂, —S(O)₂-phenyl,—S(O)₂CH₂-pyridyl, —S(O)₂-cyclopentyl, —S(O)₂-cyclopropyl,—S(O)₂-imidazolyl, —S(O)₂CH₂-tetrahydrofuranyl, —S(O)₂-pyrazolyl, butyl,—CH₂-cyclopropyl, benzyl, —CH₂CH₂CF₃, —CH₂-thiazolyl, —CH₂-oxazoyl,—CH₂-pyridyl, —CH₂-pyrimidinyl, —CH₂-pyrazolyl, —CH₂-cyclobutyl,—CH₂-cyclopropyl, —CH₂-tetrahydrofuranyl,

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

each R² is H; and

each R³ is independently selected from the group consisting of H andfluorine.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′), R⁴ isselected from the group consisting of H, methyl, ethyl, cyclopropyl,—CH₂-cyclopropyl, —CH₂F, —CHF₂, —CF₃, and —CH₂OCH₃.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′), R⁴ isselected from the group consisting of methyl, cyclopropyl, —CH₂F, and—CHF₂.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′), R⁴ isselected from the group consisting of methyl and —CHF₂.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

R¹ is methyl;

each R² is H;

each R³ is independently selected from the group consisting of H andfluorine; and

R⁴ is selected from the group consisting of methyl and —CHF₂.

The following alternatives of ring A are applicable to any of theembodiments described hereinabove.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

ring C is:

R¹ is methyl;

each R² is H;

each R³ is independently selected from the group consisting of H andfluorine; and

R⁴ is selected from the group consisting of methyl and —CHF₂.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

ring C is:

wherein each R^(N) group is selected from the group consisting of H,—C(O)CH₃, —C(O)CH₂CH₃, —C(O)CH₂CH(CH₃)₂, —C(O)-cyclopropyl,—C(O)—CH₂-cyclopropyl, —C(O)N(CH₃)₂, —C(O)NHCH₃, —S(O)₂CH₃,—S(O)₂CH₂CH₃, —S(O)₂CH₂CF₃, —S(O)₂CH₂CH(CH₃)₂, —S(O)₂-phenyl,—S(O)₂CH₂-pyridyl, —S(O)₂-cyclopentyl, —S(O)₂-cyclopropyl,—S(O)₂-imidazolyl, —S(O)₂—CH₂-tetrahydrofuranyl, —S(O)₂-pyrazolyl,—S(O)₂N(CH₃)₂, —S(O)₂NHCH₃, methyl, ethyl, propyl, cyclopropyl, butyl,—CH₂-cyclopropyl, benzyl, —CH₂OCH₃, —CH₂OCH₂CH₃, phenyl, pyridyl,pyrimidinyl, pyrazinyl, oxadiazolyl, isoxazolyl, oxazolyl, and pyrrolyl,—CH₂-thiazolyl, —CH₂-oxazoyl, —CH₂-pyridyl, —CH₂-pyrimidinyl,—CH₂-pyrazinyl, —CH₂-pyrazolyl, —CH₂-cyclobutyl, —CH₂-cyclopropyl, and—CH₂-tetrahydrofuranyl,

wherein said benzyl, cyclobutyl, phenyl, pyridyl, oxadiazolyl,imidazolyl, isoxazolyl, oxazolyl, and pyrrolyl are each optionallyunsubstituted or substituted with fluorine, chlorine, methyl, —CN, —CF₃,CHF₂, and —OMe;

R¹ is methyl;

each R² is H;

each R³ is independently selected from the group consisting of H andfluorine; and

R⁴ is selected from the group consisting of methyl and —CHF₂.

The following alternative embodiments relating to ring A and itsoptional substituents are applicable to any of the embodiments describedhereinabove.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

ring A is selected from the group consisting of phenyl, pyridazinyl,pyridyl, pyrimidinyl, pyrazinyl, triazinyl, and tetrazinyl.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

ring A is selected from the group consisting of phenyl, pyridazinyl,pyridyl, pyrimidinyl, and pyrazinyl.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

ring A is selected from the group consisting of phenyl and pyridyl.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

each R^(A) (when present) is independently selected from the groupconsisting of halogen, —CN, —SF₅, —NHCH₃, —N(CH₃)₂, —OCH₃, —OCH₂CH₃,—O-cyclopropyl, —O—CH₂-cyclopropyl, —CH₂OCH₃, —S(CH₃), methyl, ethyl,cyclopropyl, —CH₂-cyclopropyl, —CF₃, —CHF₂, —CH₂F, —OCF₃, and —OCHF₂.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

each R^(A) (when present) is independently selected from the groupconsisting of fluoro, chloro, bromo, —CN, —OCH₃, —CH₂OCH₃, methyl,cyclopropyl, —CF₃, —CHF₂, —CH₂F, —OCF₃, and —OCHF₂.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

each R^(A) (when present) is independently selected from the groupconsisting of fluoro, chloro, —CN, —OCH₃, —CH₂OCH₃, methyl, cyclopropyl,—CF₃, —CHF₂, and —CH₂F.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

ring A is selected from the group consisting of phenyl, pyridazinyl,pyridyl, pyrimidinyl, pyrazinyl, triazinyl, and tetrazinyl;

m is 0, 1, or 2; and

each R^(A) (when present) is independently selected from the groupconsisting of halogen, —CN, —SF₅, —NHCH₃, —N(CH₃)₂, —OCH₃, —OCH₂CH₃,—O-cyclopropyl, —O—CH₂-cyclopropyl, —CH₂OCH₃, —S(CH₃), methyl, ethyl,cyclopropyl, —CH₂-cyclopropyl, —CF₃, —CHF₂, —CH₂F, —OCF₃, and —OCHF₂.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

ring A is selected from the group consisting of phenyl, wherein m is 0,1, 2, or 3, and pyridyl wherein m is 0, 1, or 2; and

each R^(A) (when present) is independently selected from the groupconsisting of halogen, —CN, —SF₅, —NHCH₃, —N(CH₃)₂, —OCH₃, —OCH₂CH₃,—O-cyclopropyl, —O—CH₂-cyclopropyl, —CH₂OCH₃, —S(CH₃), methyl, ethyl,cyclopropyl, —CH₂-cyclopropyl, —CF₃, —CHF₂, —CH₂F, —OCF₃, and —OCHF₂.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

ring A is phenyl, wherein m is 0 or 1 and R^(A) (when present) isfluoro;

each R^(A) (when present) is independently selected from the groupconsisting of halogen, —CN, —SF₅, —NHCH₃, —N(CH₃)₂, —OCH₃, —OCH₂CH₃,—O-cyclopropyl, —O—CH₂-cyclopropyl, —CH₂OCH₃, —S(CH₃), methyl, ethyl,cyclopropyl, —CH₂-cyclopropyl, —CF₃, —CHF₂, —CH₂F, —OCF₃, and —OCHF₂.

It shall be understood that the phrase “m is 0 or more” means m is aninteger from 0 up to the number that corresponds to the maximum numberof substitutable hydrogen atoms of the ring to which R^(A) is shownattached.

Thus, in embodiments wherein ring A is a moiety having 4 substitutablehydrogen atoms, m is 0, 1, 2, 3, or 4. In an alternative of suchembodiments wherein ring A is a moiety having 4 substitutable hydrogenatoms, m is 0, 1, 2, or 3. In an alternative of such embodiments whereinring A is a moiety having 4 substitutable hydrogen atoms, m is 0, 1, or2. In an alternative of such embodiments wherein ring A is a moietyhaving 3 substitutable hydrogen atoms, m is 0 or 1. In alternative ofsuch embodiments wherein ring A is a moiety having 3 substitutablehydrogen atoms, m is 0.

In embodiments wherein ring A is a moiety having 3 substitutablehydrogen atoms, m is 0, 1, 2, or 3. In an alternative of suchembodiments wherein ring A is a moiety having 3 substitutable hydrogenatoms, m is 0, 1, or 2. In an alternative of such embodiments whereinring A is a moiety having 3 substitutable hydrogen atoms, m is 0 or 1.In alternative of such embodiments wherein ring A is a moiety having 3substitutable hydrogen atoms, m is 0.

In embodiments wherein ring A is a moiety having 2 substitutablehydrogen atoms, m is 0, 1, or 2. In an alternative of such embodimentswherein ring A is a moiety having 2 substitutable hydrogen atoms, m is 0or 1. In alternative of such embodiments wherein ring A is a moietyhaving 2 substitutable hydrogen atoms, m is 0.

In embodiments wherein ring A is a moiety having 1 substitutablehydrogen atom, m is 0 or 1. In an alternative of such embodimentswherein ring A is a moiety having 1 substitutable hydrogen atoms, m is0.

The following alternatives of R^(L) are applicable to any of theembodiments described hereinabove.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

R^(L) is selected from the group consisting of lower alkyl and lowerheteroalkyl, wherein said lower alkyl and lower heteroalkyl of R^(L) areeach optionally unsubstituted or substituted with one or more halogen.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

R^(L) is selected from the group consisting of methyl, ethyl, propyl,butyl, —CF₃, —CHF₂, —CH₂F, —CH₂CF₃, —CF₂CH₃, —CH₂OCH₃, —CH₂OCH₂CH₃,—CH₂CH₂OCH₃, —CH₂SCH₃, —CH₂SCH₂CH₃, —CH₂CH₂SCH₃, —CH₂N(CH₃)₂, —CH₂NHCH₃,—CH₂CH₂N(CH₃)₂, —CH₂OCF₃, and —CH₂OCHF₂.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′): R^(L)is selected from the group consisting of methyl, ethyl, —CF₃, —CHF₂,—CH₂F, —CH₂CF₃, —CF₂CH₃, —CH₂OCH₃, —CH₂OCH₂CH₃, —CH₂SCH₃, —CH₂N(CH₃)₂,—CH₂OCF₃, and —CH₂OCHF₂.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′): R^(L)is selected from the group consisting of methyl, ethyl, —CF₃, —CHF₂,—CH₂F, —CH₂CF₃, —CF₂CH₃, —CH₂OCH₃, CH₂OCF₃, and —CH₂OCHF₂.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

R^(L) is a moiety having the formula

wherein q, L_(B), ring B, p, and R^(B) are each as defined in Formula(I).

In some embodiments, in each of Formulas (I), (I′), (IA), and (IA′):

q is 0. In such embodiments, -L_(B)- is absent; R^(L) is a moiety havingthe formula

and ring B and -L₁- are directly connected as shown:

In some embodiments in each of Formulas (I), (I′), (IA), and (IA′):

q is 1; and

R^(L) is a moiety having the formula

wherein:

-L_(B)- is a divalent moiety selected from the group consisting of—CH₂—, —CF₂—, —CH₂CH₂—, —OCH₂—, and —OCF₂—.

In some embodiments in each of Formulas (I), (I′), (IA), and (IA′):

q is 1; and

R^(L) is a moiety having the formula

wherein:

-L_(B)- is a divalent moiety selected from the group consisting of—CH₂—, —CF₂—, and —CH₂CH₂—.

In some embodiments in each of Formulas (I), (I′), (IA), and (IA′):

q is 1; and

R^(L) is a moiety having the formula

wherein:

-L_(B)- is —CH₂—.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

R^(L) is a moiety having the formula

wherein:

ring B is selected from the group consisting of azetidinyl,benzimidazolyl, benzoisothiazolyl, benzoisoxazoyl, benzothiazolyl,benzoxazoyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropyl,dihydroindenyl, dihydrooxazolyl, furanyl, imidazolyl, imidazopyridinyl,imidazopyrimidinyl, indenyl, indolyl, isothiazolyl, isoxazolyl,morpholinyl, oxadiazolyl, oxazolyl, oxetanyl, phenyl, piperazinyl,piperidinyl, pyrazinyl, pyrazolyl, pyrazolopyridinyl,pyrazolopyrimidinyl, pyridazinyl, pyridyl, pyrimidinyl,pyrazolopyridinyl, pyrrolidinyl, pyrrolyl, pyrrolopyridinyl,pyrrolopyrimidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrazolyl,thiadiazolyl, thiazolyl, thienyl, thienylpyridine, thiomorpholinyl,thiomorpholinyl dioxide, and triazolyl.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

R^(L) is a moiety having the formula

wherein:

ring B is selected from the group consisting of cyclobutyl, cyclopropyl,furanyl, indolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl,oxetanyl, phenyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl,pyrimidinyl, pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl,thiadiazolyl, thiazolyl, and thienyl.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

R^(L) is a moiety having the formula

wherein:

ring B is selected from the group consisting of furanyl, indolyl,isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, phenyl, pyrazinyl,pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl,thiazolyl, and thienyl.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

R^(L) is a moiety having the formula

wherein:

ring B is selected from the group consisting of isoxazoyl, oxadiazoyl,oxazolyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, and pyrazolyl.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

R^(L) is a moiety having the formula

wherein:

each R^(B) group (when present) is independently selected from the groupconsisting of halogen, oxo, —OH, —CN, —SF₅, —NH₂, —NH(CH₃), —N(CH₃)₂,—NHC(O)CH₃, —N(CH₃)C(O)CH₃, —NHS(O)₂CH₃, —N(CH₃)S(O)₂CH₃, —C(O)OCH₃,—C(O)OCH₂CH₃, —C(O)N(CH₃)₂, —C(O)NHCH₃, —S(O)₂CH₃, —S(O)₂N(CH₃)₂,—S(O)₂NHCH₃, —OCH₃, —OCH₂CH₃, —O-cyclopropyl, —O—CH₂-cyclopropyl,—OCH₂—C≡C—H, —OCH₂—C≡C—CH₃, —S(CH₃), methyl, ethyl, propyl, cyclopropyl,—CH₂-cyclopropyl, —CH₂OCH₃, —CH₂OCH₂CH₃, —C≡CH, —C≡C—CH₃, —CF₃, —CHF₂,—CH₂F, —OCF₃, —OCH₂CF₃, —OCHF₂, —OCH₂F, —OCH₂CH₂F, phenyl, pyridyl,oxadiazoyl, isoxazoyl, oxazoyl, and pyrrolyl,

-   -   wherein each said phenyl, pyridyl, oxadiazoyl, isoxazoyl,        oxazoyl, and pyrrolyl is optionally substituted with from 1 to 3        substituents independently selected from the group consisting of        F, Cl, —CN, —CH₃, —OCH₃, and —CF₃.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

R^(L) is a moiety having the formula

wherein:

each R^(B) group (when present) is independently selected from the groupconsisting of fluoro, chloro, bromo, —OH, —CN, —SF₅, —NH₂, —NH(CH₃),—N(CH₃)₂, —NHC(O)CH₃, —N(CH₃)C(O)CH₃, —NHS(O)₂CH₃, —N(CH₃)S(O)₂CH₃,—C(O)OCH₃, —C(O)OCH₂CH₃, —C(O)N(CH₃)₂, —C(O)NHCH₃, —S(O)₂CH₃,—S(O)₂N(CH₃)₂, —S(O)₂NHCH₃, —OCH₃, —OCH₂CH₃, —O-cyclopropyl,—O—CH₂-cyclopropyl, —OCH₂—C≡C—H, —OCH₂—C≡C—CH₃, —S(CH₃), methyl, ethyl,propyl, cyclopropyl, —CH₂-cyclopropyl, —CH₂OCH₃, —CH₂OCH₂CH₃, —C≡CH,—C≡C—CH₃, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCH₂CF₃, —OCHF₂, —OCH₂F, and—OCH₂CH₂F.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

R^(L) is a moiety having the formula

wherein:

each R^(B) group (when present) is independently selected from the groupconsisting of fluoro, chloro, bromo, —CN, —S(O)₂CH₃, —OCH₃,—O-cyclopropyl, —O—CH₂-cyclopropyl, —OCH₂—C≡C—H, —OCH₂—C≡C—CH₃, methyl,cyclopropyl, —CH₂-cyclopropyl, —CH₂OCH₃, —C≡CH, —C≡C—CH₃, —CF₃, —CHF₂,—CH₂F, —OCF₃, —OCHF₂, —OCH₂F, and —OCH₂CH₂F.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

R^(L) is a moiety having the formula

wherein:

q is 0 or 1;

-L_(B)- (when present) is a divalent moiety selected from the groupconsisting of —CH₂—, —CF₂—, —CH₂CH₂—, —OCH₂—, and —OCF₂—;

ring B is selected from the group consisting of azetidinyl,benzimidazolyl, benzoisothiazolyl, benzoisoxazoyl, benzothiazolyl,benzoxazoyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropyl,dihydroindenyl, dihydrooxazolyl, furanyl, imidazolyl, imidazopyridinyl,imidazopyrimidinyl, indenyl, indolyl, isothiazolyl, isoxazolyl,morpholinyl, oxadiazolyl, oxazolyl, oxetanyl, phenyl, piperazinyl,piperidinyl, pyrazinyl, pyrazolyl, pyrazolopyridinyl,pyrazolopyrimidinyl, pyridazinyl, pyridyl, pyrimidinyl,pyrazolopyridinyl, pyrrolidinyl, pyrrolyl, pyrrolopyridinyl,pyrrolopyrimidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrazolyl,thiadiazolyl, thiazolyl, thienyl, thienylpyridine, thiomorpholinyl,thiomorpholinyl dioxide, and triazolyl;

p is 0 or more; and

each R^(B) group (when present) is independently selected from the groupconsisting of halogen, oxo, —OH, —CN, —SF₅, —NH₂, —NH(CH₃), —N(CH₃)₂,—NHC(O)CH₃, —N(CH₃)C(O)CH₃, —NHS(O)₂CH₃, —N(CH₃)S(O)₂CH₃, —C(O)OCH₃,—C(O)OCH₂CH₃, —C(O)N(CH₃)₂, —C(O)NHCH₃, —S(O)₂CH₃, —S(O)₂N(CH₃)₂,—S(O)₂NHCH₃, —OCH₃, —OCH₂CH₃, —O-cyclopropyl, —O—CH₂-cyclopropyl,—OCH₂—C≡C—H, —OCH₂—C≡C—CH₃, —S(CH₃), methyl, ethyl, propyl, cyclopropyl,—CH₂-cyclopropyl, —CH₂OCH₃, —CH₂OCH₂CH₃, —C≡CH, —C≡C—CH₃, —CF₃, —CHF₂,—CH₂F, —OCF₃, —OCH₂CF₃, —OCHF₂, —OCH₂F, —OCH₂CH₂F, phenyl, pyridyl,oxadiazoyl, isoxazoyl, oxazoyl, and pyrrolyl,

-   -   wherein each said phenyl, pyridyl, oxadiazoyl, isoxazoyl,        oxazoyl, and pyrrolyl is optionally substituted with from 1 to 3        substituents independently selected from the group consisting of        F, Cl, CN, —CH₃, —OCH₃, and —CF₃.

In an alternative of the immediately preceding embodiment, q is 0.

In another alternative of the immediately preceding embodiment, q is 1;and

-L_(B)- is a divalent moiety selected from the group consisting of—CH₂—, —CF₂—, and —CH₂CH₂—.

In another alternative of the immediately preceding embodiment, q is 1;and

-L_(B)- is —CH₂—.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

R^(L) is a moiety having the formula

wherein:

q is 0 or 1;

-L_(B)- (when present) is a divalent moiety selected from the groupconsisting of —CH₂—, —CF₂—, —CH₂CH₂—, —OCH₂—, and —OCF₂—;

ring B is selected from the group consisting of cyclobutyl, cyclopropyl,furanyl, indolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl,oxetanyl, phenyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl,pyrimidinyl, pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl,thiadiazolyl, thiazolyl, and thienyl;

p is 0 or more; and

each R^(B) group (when present) is independently selected from the groupconsisting of fluoro, chloro, bromo, —OH, —CN, —SF₅, —NH₂, —NH(CH₃),—N(CH₃)₂, —NHC(O)CH₃, —N(CH₃)C(O)CH₃, —NHS(O)₂CH₃, —N(CH₃)S(O)₂CH₃,—C(O)OCH₃, —C(O)OCH₂CH₃, —C(O)N(CH₃)₂, —C(O)NHCH₃, —S(O)₂CH₃,—S(O)₂N(CH₃)₂, —S(O)₂NHCH₃, —OCH₃, —OCH₂CH₃, —O-cyclopropyl,—O—CH₂-cyclopropyl, —OCH₂—C≡C—H, —OCH₂—C≡C—CH₃, —S(CH₃), methyl, ethyl,propyl, cyclopropyl, —CH₂-cyclopropyl, —CH₂OCH₃, —CH₂OCH₂CH₃, —C≡CH,—C≡C—CH₃, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCH₂CF₃, —OCHF₂, —OCH₂F, and—OCH₂CH₂F.

In an alternative of the immediately preceding embodiment, q is 0.

In another alternative of the immediately preceding embodiment, q is 1;and

-L_(B)- is a divalent moiety selected from the group consisting of—CH₂—, —CF₂—, and —CH₂CH₂—.

In another alternative of the immediately preceding embodiment, q is 1;and

-L_(B)- is —CH₂—.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

q is 1; and R^(L) is a moiety having the formula

wherein:

-L_(B)- (when present) is a divalent moiety selected from the groupconsisting of —CH₂—, —CF₂—, —CH₂CH₂—, —OCH₂—, and —OCF₂—.

ring B is selected from the group consisting of isoxazoyl, oxadiazoyl,oxazolyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, and pyrazolyl;

p is 0 or more; and

each R^(B) group (when present) is independently selected from the groupconsisting of fluoro, chloro, bromo, —CN, —S(O)₂CH₃, —OCH₃,—O-cyclopropyl, —O—CH₂-cyclopropyl, —OCH₂—C≡C—H, —OCH₂—C≡C—CH₃, methyl,cyclopropyl, —CH₂-cyclopropyl, —CH₂OCH₃, —C≡CH, —C≡C—CH₃, —CF₃, —CHF₂,—CH₂F, —OCF₃, —OCHF₂, —OCH₂F, and —OCH₂CH₂F.

In an alternative of the immediately preceding embodiment, -L_(B)- is adivalent moiety selected from the group consisting of —CH₂—, —CF₂—, and—CH₂CH₂—.

In another alternative of the immediately preceding embodiment, -L_(B)-is —CH₂—.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

q is 0; and R^(L) is a moiety having the formula

wherein:

ring B is selected from the group consisting of isoxazoyl, oxadiazoyl,oxazolyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, and pyrazolyl;

p is 0 or more; and

each R^(B) group (when present) is independently selected from the groupconsisting of fluoro, chloro, bromo, —CN, —S(O)₂CH₃, —OCH₃,—O-cyclopropyl, —O—CH₂-cyclopropyl, —OCH₂—C≡C—H, —OCH₂—C≡C—CH₃, methyl,cyclopropyl, —CH₂-cyclopropyl, —CH₂OCH₃, —C≡CH, —C≡C—CH₃, —CF₃, —CHF₂,—CH₂F, —OCF₃, —OCHF₂, —OCH₂F, and —OCH₂CH₂F.

In one embodiment, in each of Formulas (I), (I′), (IA), and (IA′):

q is 0; and R^(L) is a moiety having the formula

wherein:

ring B is selected from the group consisting of pyridyl and pyrazinyl;

p is 0 or 1; and

each R^(B) group (when present) is independently selected from the groupconsisting of fluoro, chloro, bromo, —CN, —S(O)₂CH₃, —OCH₃,—O-cyclopropyl, —O—CH₂-cyclopropyl, —OCH₂—C≡C—H, —OCH₂—C≡C—CH₃, methyl,cyclopropyl, —CH₂-cyclopropyl, —CH₂OCH₃, —C≡CH, —C≡C—CH₃, —CF₃, —CHF₂,—CH₂F, —OCF₃, —OCHF₂, —OCH₂F, and —OCH₂CH₂F.

It shall be understood that the phrase “p is 0 or more” means p is aninteger from 0 up to the number that corresponds to the maximum numberof substitutable hydrogen atoms of the ring to which R^(B) is shownattached.

Thus, in embodiments wherein ring B is a moiety having 4 substitutablehydrogen atoms, p is 0, 1, 2, 3, or 4. In an alternative of suchembodiments wherein ring B is a moiety having 4 substitutable hydrogenatoms, p is 0, 1, 2, or 3. In an alternative of such embodiments whereinring B is a moiety having 4 substitutable hydrogen atoms, p is 0, 1, or2. In an alternative of such embodiments wherein ring B is a moietyhaving 3 substitutable hydrogen atoms, p is 0 or 1. In alternative ofsuch embodiments wherein ring B is a moiety having 3 substitutablehydrogen atoms, p is 0.

In embodiments wherein ring B is a moiety having 3 substitutablehydrogen atoms, p is 0, 1, 2, or 3. In an alternative of suchembodiments wherein ring B is a moiety having 3 substitutable hydrogenatoms, p is 0, 1, or 2. In an alternative of such embodiments whereinring B is a moiety having 3 substitutable hydrogen atoms, p is 0 or 1.In alternative of such embodiments wherein ring B is a moiety having 3substitutable hydrogen atoms, p is 0.

In embodiments wherein ring B is a moiety having 2 substitutablehydrogen atoms, p is 0, 1, or 2. In an alternative of such embodimentswherein ring B is a moiety having 2 substitutable hydrogen atoms, p is 0or 1. In alternative of such embodiments wherein ring B is a moietyhaving 2 substitutable hydrogen atoms, p is 0.

In embodiments wherein ring B is a moiety having 1 substitutablehydrogen atom, p is 0 or 1. In an alternative of such embodimentswherein ring B is a moiety having 1 substitutable hydrogen atoms, p is0.

In an alternative of each of the embodiments described above, -L₁- is—C(O)NH—.

As noted above, -L₁- (and -L_(B)- when present) represent divalentmoieties. The orientation of such divalent moieties in the formula isthe same as the orientation of the moiety as written. Thus, for example,when R^(L) is the moiety

and -L₁- is a —C(O)NH— group, the moiety

has the formula:

Specific non-limiting examples of compounds of the invention are shownin the table of examples below. While only one tautomeric form of eachcompound is shown in the tables, it shall be understood that alltautomeric forms of the compounds are contemplated as being within thescope of the non-limiting examples.

In another embodiment, 1 to 3 carbon atoms of the compounds of theinvention may be replaced with 1 to 3 silicon atoms so long as allvalency requirements are satisfied.

In another embodiment, there is provided a composition comprising acompound of the invention and a pharmaceutically acceptable carrier ordiluent.

Another embodiment provides a composition comprising a compound of theinvention, either as the sole active agent, or optionally in combinationwith one or more additional therapeutic agents, and a pharmaceuticallyacceptable carrier or diluent. Non-limiting examples of additionaltherapeutic agents which may be useful in combination with the compoundsof the invention include those selected from the group consisting of:(a) drugs that may be useful for the treatment of Alzheimer's diseaseand/or drugs that may be useful for treating one or more symptoms ofAlzheimer's disease, (b) drugs that may be useful for inhibiting thesynthesis Aβ, (c) drugs that may be useful for treatingneurodegenerative diseases, and (d) drugs that may be useful for thetreatment of type II diabetes and/or one or more symptoms or associatedpathologies thereof.

Non-limiting examples of additional therapeutic agents which may beuseful in combination with the compounds of the invention include drugsthat may be useful for the treatment, prevention, delay of onset,amelioration of any pathology associated with Aβ and/or a symptomthereof. Non-limiting examples of pathologies associated with Aβinclude: Alzheimer's Disease, Down's syndrome, Parkinson's disease,memory loss, memory loss associated with Alzheimer's disease, memoryloss associated with Parkinson's disease, attention deficit symptoms,attention deficit symptoms associated with Alzheimer's disease (“AD”),Parkinson's disease, and/or Down's syndrome, dementia, stroke,microgliosis and brain inflammation, pre-senile dementia, seniledementia, dementia associated with Alzheimer's disease, Parkinson'sdisease, and/or Down's syndrome, progressive supranuclear palsy,cortical basal degeneration, neurodegeneration, olfactory impairment,olfactory impairment associated with Alzheimer's disease, Parkinson'sdisease, and/or Down's syndrome, β-amyloid angiopathy, cerebral amyloidangiopathy, hereditary cerebral hemorrhage, mild cognitive impairment(“MCI”), glaucoma, amyloidosis, type II diabetes, hemodialysiscomplications (from β₂ microglobulins and complications arisingtherefrom in hemodialysis patients), scrapie, bovine spongiformencephalitis, and Creutzfeld-Jakob disease, comprising administering tosaid patient at least one compound of the invention, or a tautomer orisomer thereof, or pharmaceutically acceptable salt or solvate of saidcompound or said tautomer, in an amount effective to inhibit or treatsaid pathology or pathologies.

Non-limiting examples of additional therapeutic agents for that may beuseful in combination with compounds of the invention include:muscarinic antagonists (e.g., m₁ agonists (such as acetylcholine,oxotremorine, carbachol, or McNa343), or m₂ antagonists (such asatropine, dicycloverine, tolterodine, oxybutynin, ipratropium,methoctramine, tripitamine, or gallamine)); cholinesterase inhibitors(e.g., acetyl- and/or butyrylchlolinesterase inhibitors such asdonepezil (Aricept®,(±)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-onehydrochloride), galantamine (Razadyne®), and rivastigmine (Exelon®);N-methyl-D-aspartate receptor antagonists (e.g., Namenda® (memantineHCl, available from Forrest Pharmaceuticals, Inc.); combinations ofcholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists;gamma secretase modulators; gamma secretase inhibitors; non-steroidalanti-inflammatory agents; anti-inflammatory agents that can reduceneuroinflammation; anti-amyloid antibodies (such as bapineuzemab,Wyeth/Elan); vitamin E; nicotinic acetylcholine receptor agonists; CB1receptor inverse agonists or CB1 receptor antagonists; antibiotics;growth hormone secretagogues; histamine H3 antagonists; AMPA agonists;PDE4 inhibitors; GABA_(A) inverse agonists; inhibitors of amyloidaggregation; glycogen synthase kinase beta inhibitors; promoters ofalpha secretase activity; PDE-10 inhibitors; Tau kinase inhibitors(e.g., GSK3beta inhibitors, cdk5 inhibitors, or ERK inhibitors); Tauaggregation inhibitors (e.g., Rember®); RAGE inhibitors (e.g., TTP 488(PF-4494700)); anti-Abeta vaccine; APP ligands; agents that upregulateinsulin, cholesterol lowering agents such as HMG-CoA reductaseinhibitors (for example, statins such as Atorvastatin, Fluvastatin,Lovastatin, Mevastatin, Pitavastatin, Pravastatin, Rosuvastatin,Simvastatin) and/or cholesterol absorption inhibitors (such asEzetimibe), or combinations of HMG-CoA reductase inhibitors andcholesterol absorption inhibitors (such as, for example, Vytorin®);fibrates (such as, for example, clofibrate, Clofibride, Etofibrate, andAluminium Clofibrate); combinations of fibrates and cholesterol loweringagents and/or cholesterol absorption inhibitors; nicotinic receptoragonists; niacin; combinations of niacin and cholesterol absorptioninhibitors and/or cholesterol lowering agents (e.g., Simcor®(niacin/simvastatin, available from Abbott Laboratories, Inc.); LXRagonists; LRP mimics; H3 receptor antagonists; histone deacetylaseinhibitors; hsp90 inhibitors; 5-HT4 agonists (e.g., PRX-03140 (EpixPharmaceuticals)); 5-HT6 receptor antagonists; mGluR1 receptormodulators or antagonists; mGluR5 receptor modulators or antagonists;mGluR2/3 antagonists; Prostaglandin EP2 receptor antagonists; PAI-1inhibitors; agents that can induce Abeta efflux such as gelsolin;Metal-protein attenuating compound (e.g, PBT2); and GPR3 modulators; andantihistamines such as Dimebolin (e.g., Dimebon®, Pfizer).

Another embodiment provides a method of preparing a pharmaceuticalcomposition comprising the step of admixing at least one compound of theinvention or pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier or diluent.

Another embodiment provides a method of inhibiting β-secretasecomprising exposing a population of cells expressing β-secretase to atleast one compound of the invention, or a tautomer thereof, in an amounteffective to inhibit β-secretase. In one such embodiment, saidpopulation of cells is in vivo. In another such embodiment, saidpopulation of cells is ex vivo. In another such embodiment, saidpopulation of cells is in vitro.

Additional embodiments in which the compounds of the invention may beuseful include: a method of inhibiting β-secretase in a patient in needthereof. A method of inhibiting the formation of Aβ from APP in apatient in need thereof. A method of inhibiting the formation of Aβplaque and/or Aβ fibrils and/or Aβ oligomers and/or senile plaquesand/or neurofibrillary tangles and/or inhibiting the deposition ofamyloid protein (e.g., amyloid beta protein) in, on or aroundneurological tissue (e.g., the brain), in a patient in need thereof.Each such embodiment comprises administering at least one compound ofthe invention, or a tautomer thereof, or pharmaceutically acceptablesalt of said compound or said tautomer, in a therapeutically effectiveamount to inhibit said pathology or condition in said patient.

Additional embodiments in which the compounds of the invention may beuseful include: a method of treating, preventing, and/or delaying theonset of one or more pathologies associated with Aβ and/or one or moresymptoms of one or more pathologies associated with Aβ. Non-limitingexamples of pathologies which may be associated with Aβ include:Alzheimer's Disease, Down's syndrome, Parkinson's disease, memory loss,memory loss associated with Alzheimer's disease, memory loss associatedwith Parkinson's disease, attention deficit symptoms, attention deficitsymptoms associated with Alzheimer's disease (“AD”), Parkinson'sdisease, and/or Down's syndrome, dementia, stroke, microgliosis andbrain inflammation, pre-senile dementia, senile dementia, dementiaassociated with Alzheimer's disease, Parkinson's disease, and/or Down'ssyndrome, progressive supranuclear palsy, cortical basal degeneration,neurodegeneration, olfactory impairment, olfactory impairment associatedwith Alzheimer's disease, Parkinson's disease, and/or Down's syndrome,β-amyloid angiopathy, cerebral amyloid angiopathy, hereditary cerebralhemorrhage, mild cognitive impairment (“MCI”), glaucoma, amyloidosis,type II diabetes, hemodialysis complications (from β₂ microglobulins andcomplications arising therefrom in hemodialysis patients), scrapie,bovine spongiform encephalitis, and Creutzfeld-Jakob disease, saidmethod(s) comprising administering to said patient in need thereof atleast one compound of the invention, or a tautomer thereof, orpharmaceutically acceptable salt of said compound or said tautomer, inan amount effective to inhibit said pathology or pathologies.

Another embodiment in which the compounds of the invention may be usefulincludes a method of treating Alzheimer's disease, wherein said methodcomprises administering an effective (i.e., therapeutically effective)amount of one or more compounds of the invention (or a tautomer thereof,or pharmaceutically acceptable salt of said compound or said tautomer),optionally in further combination with one or more additionaltherapeutic agents which may be effective to treat Alzheimer's diseaseor a disease or condition associated therewith, to a patient in need oftreatment. In embodiments wherein one or more additional therapeuticagents are administered, such agents may be administered sequentially ortogether. Non-limiting examples of associated diseases or conditions,and non-limiting examples of suitable additional therapeutically activeagents, are as described above.

Another embodiment in which the compounds of the invention may be usefulincludes a method of treating mild cognitive impairment (“MCI”), whereinsaid method comprises administering an effective (i.e., therapeuticallyeffective) amount of one or more compounds of the invention (or atautomer thereof, or pharmaceutically acceptable salt of said compoundor said tautomer) to a patient in need of treatment. In one suchembodiment, treatment is commenced prior to the onset of symptoms.

Another embodiment in which the compounds of the invention may be usefulincludes a method of preventing, or alternatively of delaying the onset,of mild cognitive impairment or, in a related embodiment, of preventingor alternatively of delaying the onset of Alzheimer's disease. In suchembodiments, treatment can be initiated prior to the onset of symptoms,in some embodiments significantly before (e.g., from several months toseveral years before) the onset of symptoms to a patient at risk fordeveloping MCI or Alzheimer's disease. Thus, such methods compriseadministering, prior to the onset of symptoms or clinical or biologicalevidence of MCI or Alzheimer's disease (e.g., from several months toseveral yeards before, an effective (i.e., therapeutically effective),and over a period of time and at a frequency of dose sufficient for thetherapeutically effective degree of inhibition of the BACE enzyme overthe period of treatment, an amount of one or more compounds of theinvention (or a tautomer thereof, or pharmaceutically acceptable salt ofsaid compound or said tautomer) to a patient in need of treatment.

Another embodiment in which the compounds of the invention may be usefulincludes a method of treating Down's syndrome, comprising administeringan effective (i.e., therapeutically effective) amount of one or morecompounds of the invention (or a tautomer thereof, or pharmaceuticallyacceptable salt or solvate of said compound or said tautomer) to apatient in need of treatment.

Another embodiment in which the compounds of the invention may be usefulincludes a kit comprising, in separate containers, in a single package,pharmaceutical compositions for use in combination, wherein onecontainer comprises an effective amount of a compound of the invention(or a tautomer thereof, or pharmaceutically acceptable salt of saidcompound or said tautomer) in a pharmaceutically acceptable carrier, andanother container (i.e., a second container) comprises an effectiveamount of another pharmaceutically active ingredient, the combinedquantities of the compound of the invention and the otherpharmaceutically active ingredient being effective to: (a) treatAlzheimer's disease, or (b) inhibit the deposition of amyloid proteinin, on or around neurological tissue (e.g., the brain), or (c) treatneurodegenerative diseases, or (d) inhibit the activity of BACE-1 and/orBACE-2.

In various embodiments, the compositions and methods disclosed above andbelow wherein the compound(s) of the invention is a compound orcompounds selected from the group consisting of the exemplary compoundsof the invention described herein.

In another embodiment, the invention provides methods of treating adisease or pathology, wherein said disease or pathology is Alzheimer'sdisease, olfactory impairment associated with Alzheimer's disease,Down's syndrome, olfactory impairment associated with Down's syndrome,Parkinson's disease, olfactory impairment associated with Parkinson'sdisease, stroke, microgliosis brain inflammation, pre-senile dementia,senile dementia, progressive supranuclear palsy, cortical basaldegeneration, β-amyloid angiopathy, cerebral amyloid angiopathy,hereditary cerebral hemorrhage, mild cognitive impairment, glaucoma,amyloidosis, type II diabetes, diabetes-associated amyloidogenesis,scrapie, bovine spongiform encephalitis, traumatic brain injury, orCreutzfeld-Jakob disease, said method comprising administering acompound of the invention, or a pharmaceutically acceptable salt of saidcompound or said tautomer, to a patient in need thereof in an amounteffective to treat said disease or pathology.

In another embodiment, the invention provides for the use of any of thecompounds of the invention for use as a medicament, or in medicine, orin therapy.

In another embodiment, the invention provides for use of a compound ofthe invention for the manufacture of a medicament for the treatment of adisease or pathology, wherein said disease or pathology is Alzheimer'sdisease, olfactory impairment associated with Alzheimer's disease,Down's syndrome, olfactory impairment associated with Down's syndrome,Parkinson's disease, olfactory impairment associated with Parkinson'sdisease, stroke, microgliosis brain inflammation, pre-senile dementia,senile dementia, progressive supranuclear palsy, cortical basaldegeneration, β-amyloid angiopathy, cerebral amyloid angiopathy,hereditary cerebral hemorrhage, mild cognitive impairment, glaucoma,amyloidosis, type II diabetes, diabetes-associated amyloidogenesis,scrapie, bovine spongiform encephalitis, traumatic brain injury, orCreutzfeld-Jakob disease.

DEFINITIONS

The terms used herein have their ordinary meaning and the meaning ofsuch terms is independent at each occurrence thereof. Thatnotwithstanding and except where stated otherwise, the followingdefinitions apply throughout the specification and claims. Chemicalnames, common names and chemical structures may be used interchangeablyto describe that same structure. These definitions apply regardless ofwhether a term is used by itself or in combination with other terms,unless otherwise indicated. Hence the definition of“alkyl” applies to“alkyl” as well as the “alkyl” portion of“hydroxyalkyl”, “haloalkyl”,arylalkyl-, alkylaryl-, “alkoxy” etc.

It shall be understood that, in the various embodiments of the inventiondescribed herein, any variable not explicitly defined in the context ofthe embodiment is as defined in Formula (I). All valences not explicitlyfilled are assumed to be filled by hydrogen.

“Patient” includes both human and non-human animals. Non-human animalsinclude those research animals and companion animals such as mice,primates, monkeys, great apes, canine (e.g., dogs), and feline (e.g.,house cats).

“Pharmaceutical composition” (or “pharmaceutically acceptablecomposition”) means a composition suitable for administration to apatient. Such compositions may contain the neat compound (or compounds)of the invention or mixtures thereof, or salts, solvates, prodrugs,isomers, or tautomers thereof, or they may contain one or morepharmaceutically acceptable carriers or diluents. The term“pharmaceutical composition” is also intended to encompass both the bulkcomposition and individual dosage units comprised of more than one(e.g., two) pharmaceutically active agents such as, for example, acompound of the present invention and an additional agent selected fromthe lists of the additional agents described herein, along with anypharmaceutically inactive excipients. The bulk composition and eachindividual dosage unit can contain fixed amounts of the afore-said “morethan one pharmaceutically active agents”. The bulk composition ismaterial that has not yet been formed into individual dosage units. Anillustrative dosage unit is an oral dosage unit such as tablets, pillsand the like. Similarly, the herein-described method of treating apatient by administering a pharmaceutical composition of the presentinvention is also intended to encompass the administration of theafore-said bulk composition and individual dosage units.

“Halogen” (or “halo”) means fluorine, chlorine, bromine, or iodine.Preferred are fluorine, chlorine and bromine.

“Alkyl” means an aliphatic hydrocarbon group, which may be straight orbranched, comprising 1 to about 10 carbon atoms. “Lower alkyl” means astraight or branched alkyl group comprising 1 to about 4 carbon atoms.Branched means that one or more lower alkyl groups such as methyl, ethylor propyl, are attached to a linear alkyl chain. Non-limiting examplesof suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl,n-butyl, i-butyl, and t-butyl.

“Haloalkyl” means an alkyl as defined above wherein one or more hydrogenatoms on the alkyl is replaced by a halo group defined above.

“Heteroalkyl” means an alkyl moiety as defined above, which issubstituted by one or more (e.g., one, two, or three) moietiesindependently selected from the group consisting of: —O-alkyl, —S-alkyl,—S(O)-alkyl, —S(O)₂-alkyl, —N(H)alkyl, and —N(alkyl)₂.

“Alkenyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon double bond and which may be straight or branched andcomprising about 2 to about 10 carbon atoms in the straight or branchedchain. Branched means that one or more lower alkyl groups such asmethyl, ethyl propyl, ethenyl or propenyl are attached to a linear orbranched alkenyl chain. “Lower alkenyl” means about 2 to about 4 carbonatoms in the chain which may be straight or branched. Non-limitingexamples of suitable alkenyl groups include ethenyl, propenyl,n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.

“Alkylene” means a difunctional group obtained by removal of a hydrogenatom from an alkyl group that is defined above. Non-limiting examples ofalkylene include methylene, ethylene and propylene. More generally, thesuffix “ene” on alkyl, aryl, heterocycloalkyl, etc. indicates a divalentmoiety, e.g., —CH₂CH₂— is ethylene, and

is para-phenylene.

“Alkynyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon triple bond and which may be straight or branched andcomprising about 2 to about 10 carbon atoms in the chain. Branched meansthat one or more lower alkyl groups such as methyl, ethyl or propyl, orlower alkenyl or lower alkynyl groups, are attached to a linear alkynylchain. “Lower alkynyl” means about 2 to about 4 carbon atoms in thechain which may be straight or branched. Non-limiting examples ofsuitable alkynyl groups include ethynyl, propynyl, 2-butynyl and3-methylbutynyl.

“Alkenylene” means a difunctional group obtained by removal of ahydrogen from an alkenyl group that is defined above. Non-limitingexamples of alkenylene include —CH═CH—, —C(CH₃)═CH—, and —CH═CHCH₂—.

“Aryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 6 to about 14 carbon atoms, preferably about 6 to about10 carbon atoms. The aryl group can be optionally substituted with oneor more “ring system substituents” which may be the same or different,and are as defined herein. Non-limiting examples of suitable aryl groupsinclude phenyl and naphthyl. “Monocyclic aryl” means phenyl.

“Heteroaryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 5 to about 14 ring atoms, preferably about 5 to about10 ring atoms, in which one or more of the ring atoms is an elementother than carbon, for example nitrogen, oxygen or sulfur, alone or incombination. Preferred heteroaryls contain about 5 to about 6 ringatoms. The “heteroaryl” can be optionally substituted by one or moresubstituents, which may be the same or different, as defined herein. Theprefix aza, oxa or thia before the heteroaryl root name means that atleast a nitrogen, oxygen or sulfur atom respectively, is present as aring atom. A nitrogen atom of a heteroaryl can be optionally oxidized tothe corresponding N-oxide. “Heteroaryl” may also include a heteroaryl asdefined above fused to an aryl as defined above. Non-limiting examplesof suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl(which alternatively may be referred to as thiophenyl), pyrimidinyl,pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl,oxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, pyrazolyl, furazanyl,pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl,pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl,imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl,indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl,imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl,pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl,1,2,4-triazinyl, benzothiazolyl and the like. The term “heteroaryl” alsorefers to partially saturated heteroaryl moieties such as, for example,tetrahydroisoquinolyl, tetrahydroquinolyl and the like. The term“monocyclic heteroaryl” refers to monocyclic versions of heteroaryl asdescribed above and includes 4- to 7-membered monocyclic heteroarylgroups comprising from 1 to 4 ring heteroatoms, said ring heteroatomsbeing independently selected from the group consisting of N, O, and S,and oxides thereof. The point of attachment to the parent moiety is toany available ring carbon or ring heteroatom. Non-limiting examples ofmonocyclic heteroaryl moities include pyridyl, pyrazinyl, furanyl,thienyl, pyrimidinyl, pyridazinyl, pyridoneyl, thiazolyl, isothiazolyl,oxazolyl, oxadiazolyl, isoxazolyl, pyrazolyl, furazanyl, pyrrolyl,pyrazolyl, triazolyl, thiadiazolyl (e.g., 1,2,4-thiadiazolyl),imidazolyl, and triazinyl (e.g., 1,2,4-triazinyl), and oxides thereof.

“Cycloalkyl” means a non-aromatic monocyclic or multicyclic ring systemcomprising about 3 to about 10 carbon atoms, preferably about 3 to about6 carbon atoms. The cycloalkyl can be optionally substituted with one ormore substituents, which may be the same or different, as describedherein. Monocyclic cycloalkyl refers to monocyclic versions of thecycloalkyl moieties described herein. Non-limiting examples of suitablemonocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl,cycloheptyl and the like. Non-limiting examples of multicycliccycloalkyls include [1.1.1]-bicyclopentane, 1-decalinyl, norbornyl,adamantyl and the like.

“Cycloalkenyl” means a non-aromatic mono or multicyclic ring systemcomprising about 3 to about 10 carbon atoms, preferably about 5 to about10 carbon atoms which contain at least one carbon-carbon double bond.Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms. Thecycloalkenyl can be optionally substituted with one or moresubstituents, which may be the same or different, as described herein.The term “monocyclic cycloalkenyl” refers to monocyclic versions ofcycloalkenyl groups described herein and includes non-aromatic 3- to7-membered monocyclic cycloalkyl groups which contains one or morecarbon-carbon double bonds. Non-limiting examples include cyclopropenyl,cyclobutenyl, cyclopentenyl, cyclohexenyl, cyclohetpenyl,cyclohepta-1,3-dienyl, and the like. Non-limiting example of a suitablemulticyclic cycloalkenyl is norbornylenyl.

“Heterocycloalkyl” (or “heterocyclyl”) means a non-aromatic saturatedmonocyclic or multicyclic ring system comprising about 3 to about 10ring atoms, preferably about 5 to about 10 ring atoms, in which one ormore of the atoms in the ring system is an element other than carbon,for example nitrogen, oxygen or sulfur, alone or in combination. Thereare no adjacent oxygen and/or sulfur atoms present in the ring system.Preferred heterocyclyls contain about 5 to about 6 ring atoms. Theprefix aza, oxa or thia before the heterocyclyl root name means that atleast a nitrogen, oxygen or sulfur atom respectively is present as aring atom. Any —NH in a heterocyclyl ring may exist protected such as,for example, as an —N(Boc), —N(CBz), —N(Tos) group and the like; suchprotections are also considered part of this invention. The heterocyclylcan be optionally substituted by one or more substituents, which may bethe same or different, as described herein. The nitrogen or sulfur atomof the heterocyclyl can be optionally oxidized to the correspondingN-oxide, S-oxide or S,S-dioxide. Thus, the term “oxide,” when it appearsin a definition of a variable in a general structure described herein,refers to the corresponding N-oxide, S-oxide, or S,S-dioxide.“Heterocyclyl” also includes rings wherein ═O replaces two availablehydrogens on the same carbon atom (i.e., heterocyclyl includes ringshaving a carbonyl group in the ring). Such ═O groups may be referred toherein as “oxo.” An example of such a moiety is pyrrolidinone (orpyrrolidone):

As used herein, the term “monocyclic heterocycloalkyl” refers monocyclicversions of the heterocycloalkyl moities described herein and include a4- to 7-membered monocyclic heterocycloalkyl groups comprising from 1 to4 ring heteroatoms, said ring heteroatoms being independently selectedfrom the group consisting of N, N-oxide, O, S, S-oxide, S(O), and S(O)₂.The point of attachment to the parent moiety is to any available ringcarbon or ring heteroatom. Non-limiting examples of monocyclicheterocycloalkyl groups include piperidyl, oxetanyl, pyrrolyl,piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl,tetrahydrofuranyl, tetrahydrothiophenyl, beta lactam, gamma lactam,delta lactam, beta lactone, gamma lactone, delta lactone, andpyrrolidinone, and oxides thereof. Non-limiting examples of loweralkyl-substituted oxetanyl include the moiety:

“Heterocycloalkenyl” (or “heterocyclenyl”) means a non-aromaticmonocyclic or multicyclic ring system comprising about 3 to about 10ring atoms, preferably about 5 to about 10 ring atoms, in which one ormore of the atoms in the ring system is an element other than carbon,for example nitrogen, oxygen or sulfur atom, alone or in combination,and which contains at least one carbon-carbon double bond orcarbon-nitrogen double bond. There are no adjacent oxygen and/or sulfuratoms present in the ring system. Preferred heterocyclenyl rings containabout 5 to about 6 ring atoms. The prefix aza, oxa or thia before theheterocyclenyl root name means that at least a nitrogen, oxygen orsulfur atom respectively is present as a ring atom. The heterocyclenylcan be optionally substituted by one or more substituents, which may bethe same or different, as described herein. The nitrogen or sulfur atomof the heterocyclenyl can be optionally oxidized to the correspondingN-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitableheterocyclenyl groups include 1,2,3,4-tetrahydropyridinyl,1,2-dihydropyridinyl, 1,4-dihydropyridinyl, 1,2,3,6-tetrahydropyridinyl,1,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl, 3-pyrrolinyl,2-imidazolinyl, 2-pyrazolinyl, dihydroimidazolyl, dihydrooxazolyl,dihydrooxadiazolyl, dihydrothiazolyl, 3,4-dihydro-2H-pyranyl,dihydrofuranyl, fluorodihydrofuranyl, 7-oxabicyclo[2.2.1]heptenyl,dihydrothiophenyl, dihydrothiopyranyl, and the like. “Heterocyclenyl”also includes rings wherein ═O replaces two available hydrogens on thesame carbon atom (i.e., heterocyclyl includes rings having a carbonylgroup in the ring). Example of such moiety is pyrrolidinone (orpyrrolone):

As used herein, the term “monocyclic heterocycloalkenyl” refers tomonocyclic versions of the heterocycloalkenyl moities described hereinand include 4- to 7-membered monocyclic heterocycloalkenyl groupscomprising from 1 to 4 ring heteroatoms, said ring heteroatoms beingindependently selected from the group consisting of N, N-oxide, O, S,S-oxide, S(O), and S(O)₂. The point of attachment to the parent moietyis to any available ring carbon or ring heteroatom. Non-limitingexamples of monocyclic heterocycloalkenyl groups include1,2,3,4-tetrahydropyridinyl, 1,2-dihydropyridinyl, 1,4-dihydropyridinyl,1,2,3,6-tetrahydropyridinyl, 1,4,5,6-tetrahydropyrimidinyl,2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl,dihydroimidazolyl, dihydrooxazolyl, dihydrooxadiazolyl,dihydrothiazolyl, 3,4-dihydro-2H-pyranyl, dihydrofuranyl,fluorodihydrofuranyl, dihydrothiophenyl, and dihydrothiopyranyl, andoxides thereof.

It should be noted that in hetero-atom containing ring systems of thisinvention, there are no hydroxyl groups on carbon atoms adjacent to a N,O or S, as well as there are no N or S groups on carbon adjacent toanother heteroatom.

there is no —OH attached directly to carbons marked 2 and 5.

“Arylalkyl” (or “aralkyl”) means an aryl-alkyl- group in which the aryland alkyl are as previously described, except that in this context the“alkyl” portion of the “arylalkyl” (or “-alkyl-aryl”) group refers to astraight or branched lower alkyl group. Preferred aralkyls comprise alower alkyl group. Non-limiting examples of suitable aralkyl groupsinclude benzyl, 2-phenethyl and naphthalenylmethyl. The bond to theparent moiety is through the alkyl. The term (and similar terms) may bewritten as “arylalkyl-” (or as “-alkyl-aryl”) to indicate the point ofattachment to the parent moiety. Similarly, “heteroarylalkyl”,“cycloalkylalkyl”, “cycloalkenylalkyl”, “heterocycloalkylalkyl”,“heterocycloalkenylalkyl”, etc., mean a heteroaryl, cycloalkyl,cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, etc. as describedherein bound to a parent moiety through an alkyl group. As indicatedabove, the “alkyl” group in this context represents a lower alkyl group,which may be straight or branched, or unsubstituted and/or substitutedas described herein.

“Alkylaryl” means an alkyl-aryl- group in which the alkyl and aryl areas previously described. Preferred alkylaryls comprise a lower alkylgroup. Non-limiting example of a suitable alkylaryl group is tolyl. Thebond to the parent moiety is through the aryl.

“Cycloalkylether” means a non-aromatic ring of 3 to 7 members comprisingan oxygen atom and 2 to 7 carbon atoms. Ring carbon atoms can besubstituted, provided that substituents adjacent to the ring oxygen donot include halo or substituents joined to the ring through an oxygen,nitrogen or sulfur atom.

“Cycloalkylalkyl” means a cycloalkyl moiety as defined above linked viaan alkyl moiety (defined above) to a parent core. Non-limiting examplesof suitable cycloalkylalkyls include cyclohexylmethyl, adamantylmethyl,adamantylpropyl, and the like.

“Cycloalkenylalkyl” means a cycloalkenyl moiety as defined above linkedvia an alkyl moiety (defined above) to a parent core. Non-limitingexamples of suitable cycloalkenylalkyls include cyclopentenylmethyl,cyclohexenylmethyl and the like.

“Heteroarylalkyl” means a heteroaryl moiety as defined above linked viaan alkyl moiety (defined above) to a parent core. Non-limiting examplesof suitable heteroaryls include 2-pyridinylmethyl, quinolinylmethyl andthe like.

“Heterocyclylalkyl” (or “heterocycloalkylalkyl”) means a heterocyclylmoiety as defined above linked via an alkyl moiety (defined above) to aparent core. Non-limiting examples of suitable heterocyclylalkylsinclude piperidinylmethyl, piperazinylmethyl and the like.

“Heterocyclenylalkyl” means a heterocyclenyl moiety as defined abovelinked via an alkyl moiety (defined above) to a parent core.

“Alkynylalkyl” means an alkynyl-alkyl- group in which the alkynyl andalkyl are as previously described. Preferred alkynylalkyls contain alower alkynyl and a lower alkyl group. The bond to the parent moiety isthrough the alkyl. Non-limiting examples of suitable alkynylalkyl groupsinclude propargylmethyl.

“Heteroaralkyl” means a heteroaryl-alkyl- group in which the heteroaryland alkyl are as previously described. Preferred heteroaralkyls containa lower alkyl group. Non-limiting examples of suitable aralkyl groupsinclude pyridylmethyl, and quinolin-3-ylmethyl. The bond to the parentmoiety is through the alkyl.

“Hydroxyalkyl” means a HO-alkyl- group in which alkyl is as previouslydefined. Preferred hydroxyalkyls contain lower alkyl. Non-limitingexamples of suitable hydroxyalkyl groups include hydroxymethyl and2-hydroxyethyl.

“Alkoxy” means an alkyl-O— group in which the alkyl group is aspreviously described. Non-limiting examples of suitable alkoxy groupsinclude methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond tothe parent moiety is through the ether oxygen.

“Alkyoxyalkyl” means a group derived from an alkoxy and alkyl as definedherein. The bond to the parent moiety is through the alkyl.

Any of the foregoing functional groups may be unsubstituted orsubstituted as described herein. The term “substituted” means that oneor more hydrogens on the designated atom is replaced with a selectionfrom the indicated group, provided that the designated atom's normalvalency under the existing circumstances is not exceeded, and that thesubstitution results in a stable compound. Combinations of substituentsand/or variables are permissible only if such combinations result instable compounds. By “stable compound’ or “stable structure” is meant acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent.

The term “optionally substituted” means optional substitution with thespecified groups, radicals or moieties.

Substitution on a cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl,heteroarylalkyl, arylfused cycloalkylalkyl- moiety or the like includessubstitution on any ring portion and/or on the alkyl portion of thegroup.

When a variable appears more than once in a group, e.g., R⁶ in —N(R⁶)₂,or a variable appears more than once in a structure presented herein,the variables can be the same or different.

The line

as a bond generally indicates a mixture of, or either of, the possibleisomers, e.g., containing (R)- and (S)-stereochemistry. For example:

means containing both

The wavy line

, as used herein, indicates a point of attachment to the rest of thecompound. Lines drawn into the ring systems, such as, for example:

indicate that the indicated line (bond) may be attached to any of thesubstitutable ring carbon atoms.

“Oxo” is defined as a oxygen atom that is double bonded to a ring carbonin a cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclenyl, or otherring described herein, e.g.,

In this specification, where there are multiple oxygen and/or sulfuratoms in a ring system, there cannot be any adjacent oxygen and/orsulfur present in said ring system.

As well known in the art, a bond drawn from a particular atom wherein nomoiety is depicted at the terminal end of the bond indicates a methylgroup bound through that bond to the atom, unless stated otherwise. Forexample:

In another embodiment, the compounds of the invention, and/orcompositions comprising them, are present in isolated and/or purifiedform. The term “purified”, “in purified form” or “in isolated andpurified form” for a compound refers to the physical state of saidcompound after being isolated from a synthetic process (e.g. from areaction mixture), or natural source or combination thereof. Thus, theterm “purified”, “in purified form” or “in isolated and purified form”for a compound refers to the physical state of said compound (or atautomer thereof, or pharmaceutically acceptable salt of said compoundor said tautomer) after being obtained from a purification process orprocesses described herein or well known to the skilled artisan (e.g.,chromatography, recrystallization and the like), in sufficient purity tobe suitable for in vivo or medicinal use and/or characterizable bystandard analytical techniques described herein or well known to theskilled artisan.

When a functional group in a compound is termed “protected”, this meansthat the group is in modified form to preclude undesired side reactionsat the protected site when the compound is subjected to a reaction.Suitable protecting groups will be recognized by those with ordinaryskill in the art as well as by reference to standard textbooks such as,for example, T. W. Greene et al, Protective Groups in organic Synthesis(1991), Wiley, New York.

Those skilled in the art will recognize those instances in which thecompounds of the invention may be converted to prodrugs and/or solvates,another embodiment of the present invention. A discussion of prodrugs isprovided in T. Higuchi and V. Stella, Pro-drugs as Novel DeliverySystems (1987) 14 of the A.C.S. Symposium Series, and in BioreversibleCarriers in Drug Design, (1987) Edward B. Roche, ed., AmericanPharmaceutical Association and Pergamon Press. The term “prodrug” meansa compound (e.g, a drug precursor) that is transformed in vivo to yielda compound of the invention or a pharmaceutically acceptable salt,hydrate or solvate of the compound. The transformation may occur byvarious mechanisms (e.g., by metabolic or chemical processes), such as,for example, through hydrolysis in blood. A discussion of the use ofprodrugs is provided by T. Higuchi and W. Stella, “Pro-drugs as NovelDelivery Systems,” Vol. 14 of the A.C.S. Symposium Series, and inBioreversible Carriers in Drug Design, ed. Edward B. Roche, AmericanPharmaceutical Association and Pergamon Press, 1987.

One or more compounds of the invention may exist in unsolvated as wellas solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like, and it is intended that the inventionembrace both solvated and unsolvated forms where they exist. “Solvate”means a physical association of a compound of the invention with one ormore solvent molecules. This physical association involves varyingdegrees of ionic and covalent bonding, including hydrogen bonding. Incertain instances the solvate will be capable of isolation, for examplewhen one or more solvent molecules are incorporated in the crystallattice of the crystalline solid. “Solvate” encompasses bothsolution-phase and isolatable solvates. Non-limiting examples ofsuitable solvates include ethanolates, methanolates, and the like.“Hydrate” is a solvate wherein the solvent molecule is H₂O.

“Effective amount” or “therapeutically effective amount” is meant todescribe an amount of compound or a composition of the present inventioneffective in inhibiting the above-noted diseases and thus producing thedesired therapeutic, ameliorative, inhibitory or preventative effect.

Those skilled in the art will recognize those instances in which thecompounds of the invention may form salts. In such instances, anotherembodiment provides pharmaceutically acceptable salts of the compoundsof the invention. Thus, reference to a compound of the invention hereinis understood to include reference to salts thereof, unless otherwiseindicated. The term “salt(s)”, as employed herein, denotes any of thefollowing: acidic salts formed with inorganic and/or organic acids, aswell as basic salts formed with inorganic and/or organic bases. Inaddition, when a compound of the invention contains both a basic moiety,such as, but not limited to a pyridine or imidazole, and an acidicmoiety, such as, but not limited to a carboxylic acid, zwitterions(“inner salts”) may be formed and are included within the term “salt(s)”as used herein. Pharmaceutically acceptable (i.e., non-toxic,physiologically acceptable) salts are preferred, although other saltsare also potentially useful. Salts of the compounds of the invention maybe formed by methods known to those of ordinary skill in the art, forexample, by reacting a compound of the invention with an amount of acidor base, such as an equivalent amount, in a medium such as one in whichthe salt precipitates or in an aqueous medium followed bylyophilization.

Exemplary acid addition salts which may be useful include acetates,ascorbates, benzoates, benzenesulfonates, bisulfates, borates,butyrates, citrates, camphorates, camphorsulfonates, fumarates,hydrochlorides, hydrobromides, hydroiodides, lactates, maleates,methanesulfonates, naphthalenesulfonates, nitrates, oxalates,phosphates, propionates, salicylates, succinates, sulfates, tartarates,thiocyanates, toluenesulfonates (also known as tosylates) and the like.Additionally, acids which are generally considered suitable for theformation of pharmaceutically useful salts from basic pharmaceuticalcompounds are discussed, for example, by P. Stahl et al, Camille G.(eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use.(2002) Zurich: Wiley-VCH; S. Berge et al, Journal of PharmaceuticalSciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics(1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry(1996), Academic Press, New York; and in The Orange Book (Food & DrugAdministration, Washington, D.C. on their website). These disclosuresare incorporated herein by reference thereto.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, salts with organic bases (for example,organic amines) such as dicyclohexylamines, t-butyl amines, and saltswith amino acids such as arginine, lysine and the like. Basicnitrogen-containing groups may be quarternized with agents such as loweralkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides andiodides), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutylsulfates), long chain halides (e.g. decyl, lauryl, and stearylchlorides, bromides and iodides), aralkyl halides (e.g. benzyl andphenethyl bromides), and others.

All such acid salts and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and basesalts are considered as potentially useful alternatives to the freeforms of the corresponding compounds for purposes of the invention.

Another embodiment which may be useful includes pharmaceuticallyacceptable esters of the compounds of the invention. Such esters mayinclude the following groups: (1) carboxylic acid esters obtained byesterification of the hydroxy groups, in which the non-carbonyl moietyof the carboxylic acid portion of the ester grouping is selected fromstraight or branched chain alkyl (for example, acetyl, n-propyl,t-butyl, or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl(for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl(for example, phenyl optionally substituted with, for example, halogen,C₁₋₄alkyl, or C₁₋₄alkoxy or amino); (2) sulfonate esters, such as alkyl-or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters(for example, L-valyl or L-isoleucyl); (4) phosphonate esters and (5)mono-, di- or triphosphate esters. The phosphate esters may be furtheresterified by, for example, a C₁₋₂₀ alcohol or reactive derivativethereof, or by a 2,3-di (C₆₋₂₄)acyl glycerol.

As mentioned herein, under certain conditions the compounds of theinvention may form tautomers. Such tautomers, when present, compriseanother embodiment of the invention. It shall be understood that alltautomeric forms of such compounds are within the scope of the compoundsof the invention. For example, all keto-enol and imine-enamine forms ofthe compounds, when present, are included in the invention.

The compounds of the invention may contain asymmetric or chiral centers,and, therefore, exist in different stereoisomeric forms. It is intendedthat all stereoisomeric forms of the compounds of the invention as wellas mixtures thereof, including racemic mixtures, form part of thepresent invention. In addition, the present invention embraces allgeometric and positional isomers. For example, if a compound of theinvention incorporates a double bond or a fused ring, both the cis- andtrans-forms, as well as mixtures, are embraced within the scope of theinvention.

Where various stereoisomers of the compounds of the invention arepossible, another embodiment provides for diastereomeric mixtures andindividual enantiomers of the compounds of the invention. Diastereomericmixtures can be separated into their individual diastereomers on thebasis of their physical chemical differences by methods well known tothose skilled in the art, such as, for example, by chromatography and/orfractional crystallization. Enantiomers can be separated by convertingthe enantiomeric mixture into a diastereomeric mixture by reaction withan appropriate optically active compound (e.g., chiral auxiliary such asa chiral alcohol or Mosher's acid chloride), separating thediastereomers and converting (e.g., hydrolyzing) the individualdiastereomers to the corresponding pure enantiomers. Also, some of thecompounds of the invention may be atropisomers (e.g., substitutedbiaryls) and are considered as part of this invention. Enantiomers canalso be separated by use of chiral HPLC column.

All stereoisomers (for example, geometric isomers, optical isomers andthe like) of the compounds of the invention (including those of thesalts, solvates, esters and prodrugs of the compounds as well as thesalts, solvates and esters of the prodrugs), such as those which mayexist due to asymmetric carbons on various substituents, includingenantiomeric forms (which may exist even in the absence of asymmetriccarbons), rotameric forms, atropisomers, and diastereomeric forms, arecontemplated as embodiments within the scope of this invention, as arepositional isomers (such as, for example, 4-pyridyl and 3-pyridyl). (Forexample, if a compound of the invention incorporates a double bond or afused ring, both the cis- and trans-forms, as well as mixtures, areembraced within the scope of the invention. Also, for example, allketo-enol and imine-enamine forms of the compounds are included in theinvention.).

Individual stereoisomers of the compounds of the invention may, forexample, be substantially free of other isomers, or may be admixed, forexample, as racemates or with all other, or other selected,stereoisomers. The chiral centers of the present invention can have theS or R configuration as defined by the IUPAC 1974 Recommendations. Theuse of the terms “salt”, “solvate”, “ester”, “prodrug” and the like, isintended to equally apply to the salt, solvate, ester and prodrug ofenantiomers, stereoisomers, rotamers, tautomers, positional isomers,racemates or prodrugs of the inventive compounds.

Another embodiment which may be useful include isotopically-labelledcompounds of the invention. Such compounds are identical to thoserecited herein, but for the fact that one or more atoms are replaced byan atom having an atomic mass or mass number different from the atomicmass or mass number usually found in nature. Examples of isotopes thatcan be incorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine,such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and³⁶Cl, respectively.

In the compounds of the invention, the atoms may exhibit their naturalisotopic abundances, or one or more of the atoms may be artificiallyenriched in a particular isotope having the same atomic number, but anatomic mass or mass number different from the atomic mass or mass numberpredominantly found in nature. The present invention is meant to includeall suitable isotopic variations of the compounds of the invention. Forexample, different isotopic forms of hydrogen (H) include protium (¹H)and deuterium (²H). Protium is the predominant hydrogen isotope found innature. Enriching for deuterium may afford certain therapeuticadvantages, such as increasing in vivo half-life or reducing dosagerequirements, or may provide a compound useful as a standard forcharacterization of biological samples. Isotopically-enriched compoundsof the invention can be prepared without undue experimentation byconventional techniques well known to those skilled in the art or byprocesses analogous to those described in the schemes and examplesherein using appropriate isotopically-enriched reagents and/orintermediates.

Polymorphic forms of the compounds of the invention, and of the salts,solvates, esters and prodrugs of the compounds of the invention, areintended to be included in the present invention.

Another embodiment provides suitable dosages and dosage forms of thecompounds of the invention. Suitable doses for administering compoundsof the invention to patients may readily be determined by those skilledin the art, e.g., by an attending physician, pharmacist, or otherskilled worker, and may vary according to patient health, age, weight,frequency of administration, use with other active ingredients, and/orindication for which the compounds are administered. Doses may rangefrom about 0.001 to 500 mg/kg of body weight/day of the compound of theinvention. In one embodiment, the dosage is from about 0.01 to about 25mg/kg of body weight/day of a compound of the invention, or apharmaceutically acceptable salt or solvate of said compound. In anotherembodiment, the quantity of active compound in a unit dose ofpreparation may be varied or adjusted from about 1 mg to about 100 mg,preferably from about 1 mg to about 50 mg, more preferably from about 1mg to about 25 mg, according to the particular application. In anotherembodiment, a typical recommended daily dosage regimen for oraladministration can range from about 1 mg/day to about 500 mg/day,preferably 1 mg/day to 200 mg/day, in two to four divided doses.

When used in combination with one or more additional therapeutic agents,the compounds of this invention may be administered together orsequentially. When administered sequentially, compounds of the inventionmay be administered before or after the one or more additionaltherapeutic agents, as determined by those skilled in the art or patientpreference.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the dosage range described herein andthe other pharmaceutically active agent or treatment within its dosagerange.

Accordingly, another embodiment provides combinations comprising anamount of at least one compound of the invention, or a pharmaceuticallyacceptable salt, solvate, ester or prodrug thereof, and an effectiveamount of one or more additional agents described above.

Another embodiment provides for pharmaceutically acceptable compositionscomprising a compound of the invention, either as the neat chemical oroptionally further comprising additional ingredients. For preparingpharmaceutical compositions from the compounds of the invention, inert,pharmaceutically acceptable carriers can be either solid or liquid.Solid form preparations include powders, tablets, dispersible granules,capsules, cachets and suppositories. The powders and tablets may becomprised of from about 5 to about 95 percent active ingredient.Suitable solid carriers are known in the art, e.g., magnesium carbonate,magnesium stearate, talc, sugar or lactose. Tablets, powders, cachetsand capsules can be used as solid dosage forms suitable for oraladministration. Examples of pharmaceutically acceptable carriers andmethods of manufacture for various compositions may be found in A.Gennaro (ed.), Remington's Pharmaceutical Sciences, 18^(th) Edition,(1990), Mack Publishing Co., Easton, Pa.

Liquid form preparations include solutions, suspensions and emulsions.Non-limiting examples which may be useful include water orwater-propylene glycol solutions for parenteral injection or addition ofsweeteners and opacifiers for oral solutions, suspensions and emulsions.Liquid form preparations may also include solutions for intranasaladministration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas,e.g. nitrogen.

Also included are solid form preparations that are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

Another embodiment which may be useful includes compositions comprisinga compound of the invention formulated for transdermal delivery. Thetransdermal compositions can take the form of creams, lotions, aerosolsand/or emulsions and can be included in a transdermal patch of thematrix or reservoir type as are conventional in the art for thispurpose.

Other embodiment which may be useful includes compositions comprising acompound of the invention formulated for subcutaneous delivery or fororal delivery. In some embodiments, it may be advantageous for thepharmaceutical preparation comparing one or more compounds of theinvention be prepared in a unit dosage form. In such forms, thepreparation may be subdivided into suitably sized unit doses containingappropriate quantities of the active component, e.g., an effectiveamount to achieve the desired purpose. Each of the foregoingalternatives, together with their corresponding methods of use, areconsidered as included in the various embodiments of the invention.

PREPARATIVE EXAMPLES

Compounds of the invention can be made using procedures known in theart. The following reaction schemes show typical procedures, but thoseskilled in the art will recognize that other procedures can also besuitable. Reactions may involve monitoring for consumption of startingmaterial, and there are many methods for such monitoring, including butnot limited to thin layer chromatography (TLC) and liquid chromatographymass spectrometry (LCMS), and those skilled in the art will recognizethat where one method is specified, other non-limiting methods may besubstituted.

Techniques, solvents and reagents may be referred to by theirabbreviations as follows:

Acetic acid: AcOH Acetic anhydride: Ac₂O Acetonitrile: MeCN Aqueous: aq.Benzyl: Bn tert-Butyl: t-Bu or tBu Centimeters: cm 3-Chloroperoxybenzoicacid: mCPBA Di-tert-butyldicarbonate: Boc₂O Dichloromethane: DCMDiisopropylamine: iPr₂NH or DIPA Diisopropylethylamine: DIEA or iPr₂NEtDimethylformamide: DMF Dimethylsulfoxide: DMSO Diphenylphosphoryl azide:DPPA Ether or diethyl ether: Et₂O Ethyl: Et Ethyl acetate: AcOEt, EtOAc,or EA Example: Ex. Grams: g O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate: HATU Hexanes: hex Highperformance liquid chromatography: HPLC Hydroxybenzotriazole: HOBtInhibition: Inh. Liquid chromatography mass Liter: L Lithiumbis(trimethylsilyl)amide: LiHMDS Spectrometry: LCMS Mass/charge ratio:m/z Methanesulfonyl chloride: MeSO₂Cl or MsCl Methanol: MeOH Methylt-butyl ether: MTBE Methyl iodide: MeI Methyl magnesium bromide: MeMgBrMicroliters: μl or μL Micrometer: μm Milligrams: mg Milliliters: mLMillimeter: mm Millimoles: mmol Micromoles: μM or uM Minutes: minn-Butyllithium: nBuLi or n-BuLi Nuclear magnetic resonance spectroscopy:NMR Number: no. or No. Para-methoxy benzyl: PMB Petroleum ether: PEPhenyl: Ph Retention time: t_(R) or Ret. Time Reverse Phase: RP Roomtemperature (ambient, about 25° C.): rt or RT tert-Butoxycarbonyl: t-Bocor Boc Trifluoroacetic acid: TFA Supercritical Fluid Chromatography: SFCTemperature: temp. Tetrahydrofuran: THF Triethylamine: Et₃N or TEA2,4,6-tripropyl-1,3,5,2,4,6- trioxatriphosphorinane-2,4-6-trioxide: T3PVolume: vMethod A

Step 1:

To a suspension of compound A1 (150 g, 0.68 mol) in CH₂Cl₂ (2200 mL) at0° C. were added oxalyl chloride (130 g, 1.03 mol) and DMF (1 mL). Themixture was stirred at 0° C. for 3 h and then concentrated in vacuo. Theresidue was dissolved in CH₂Cl₂ (2200 mL) and the resultant solution wascooled to 0° C. To the solution was added N,O-dimethylhydroxylaminehydrochloride (87 g, 0.89 mol) followed by dropwise addition of Et₃N(346 g, 3.42 mol). The mixture was warmed to RT and stirred overnight.The mixture was then poured into a separatory funnel that contained 1 NHCl_((aq.)) (2000 mL). The layers were separated and the organic layerwas washed with 1N aq. NaOH (300 mL), dried over Na₂SO₄, andconcentrated to provide compound A2.

Step 2:

To a stirred solution of compound A2 (150 g, 0.57 mol) in anhydrous THF(2000 mL) at 0° C. under an atmosphere of nitrogen was added a solutionof MeMgBr (3.0 M in Et₂O, 382 mL, 1.14 mol). The mixture was stirred at0° C. for 2 h. After that time, the solution was poured into a coldsolution of 2 N HCl_((aq.)) (2000 mL) and the mixture was allowed towarm to RT. The mixture was then extracted with ethyl acetate (1500mL×2). The combined organic layers were washed with sat. NaHCO_(3(aq.))and brine, dried over Na₂SO₄, filtered and concentrated in vacuo toafford compound A3.

Step 3:

A mixture of compound A3 (145 g, 0.67 mol),(R)-(+)-2-methyl-2-propanesulfinamide (106 g, 0.87 mol) and titanium(IV)ethoxide (274 g, 1.2 mol) in THF (1500 mL) was heated to 70° C. andstirred overnight. After that time, the reaction was cooled to 5° C. andquenched with H₂O (300 mL). The mixture was stirred at room temperaturefor 40 min and filtered. The filter cake was washed with ethyl acetate(4×2000 mL). The combined organic layers were then concentrated invacuo. The crude residue was purified by silica gel chromatography(gradient elution 100:1 to 3:1 petroleum ether:ethyl acetate) to affordcompound A4.

Method B

Step 1:

To a stirred solution of compound B1 (200 g, 1.46 mol) in pyridine (400mL) at 0° C. was added MsCl (167 g, 1.46 mol) dropwise via an additionfunnel. After the addition was completed, the mixture was stirred at RTfor 6 h and concentrated under reduced pressure. To the residue wasadded CH₂Cl₂ (1 L). The organic solution was sequentially washed with 1NHCl_((aq.)) (1 L×2), sat. NaHCO_(3(aq.)) (1 L×2), and brine (500 mL).The organic layer was dried over anhydrous Na₂SO₄, filtered, andconcentrated to afford a crude product, which was washed with petroleumether/ethyl acetate (2/1, 300 mL). The solid product was isolated byfiltration and dried under vacuum to afford compound B2.

Step 2:

To a solution of compound B2 (220 g, 1.02 mol) in DMF (1100 mL) at 0° C.was added Cs₂CO₃ (500 g, 1.53 mol) followed by dropwise addition of CH₃I(188.6 g, 1.33 mol). The mixture was stirred at RT and then poured intocold water which caused a solid to precipitate. The solid was removedvia filtration and washed with water. The solid was then dissolved inCH₂Cl₂ (3 L). The organic layer was washed with brine (500 mL), driedover anhydrous Na₂SO₄, filtered, and concentrated. The product wasfurther dried under vacuum to afford compound B3.

Method C

Step 1:

To a stirred solution of compound B3 (65 g, 284 mmol) in dry THF (1500mL) at −65° C. under an atmosphere of nitrogen was added a solution ofn-BuLi (2.5 M in hexanes, 125 mL, 312 mmol) dropwise. After stirring at−65° C. for 30 min, a solution of compound A4 (100 g, 312 mmol) in THF(500 mL) was added dropwise. The solution was stirred at −65° C. for 3 hand quenched with a sat. NH₄Cl_((aq.)) solution (300 mL). The resultantmixture was warmed to RT and stirred overnight. The mixture then wasextracted with ethyl acetate (800 mL×4) and the combined organicextracts were concentrated. The residue was purified by columnchromatography (SiO₂: gradient elution 15:1 to 3:1 petroleumether:hexanes) to afford compound C1.

Step 2:

To a solution of compound C1 (85 g, 0.15 mol) in CH₂Cl₂/MeOH (600 mL/300mL) at 0° C. was added a solution of HCl (4 M in ethyl acetate, 600 mL).The mixture was stirred at RT for 2 h and concentrated. The residue wasdissolved in CHCl₃ (850 mL) and 1,3-dimethoxybenzene (139 g, 1.0 mol)was added. To the mixture was added TFA (529 g, 4.6 mol) and theresultant mixture was stirred at RT overnight. The mixture was thenconcentrated in vacuo. The residue was partitioned between water (1000mL) and MTBE (1000 mL). The aqueous phase was separated and washed withMTBE (1000 mL×3) and then basified to pH 9 with sat. Na₂CO₃(aq.). Theaqueous layer was then extracted with CH₂Cl₂ (1000 mL×4). The organiclayers were combined, dried over anhydrous Na₂SO₄, filtered, andconcentrated to afford compound C2.

Step 3:

To a solution of compound C2 (106 g, 326 mmol) in anhydrous CH₂Cl₂ (1000mL) was added benzoyl isothiocyanate (69.07 g, 424 mmol) and theresultant mixture was stirred at RT overnight. The mixture wasconcentrated in vacuo. The residue was dissolved in methanol (500 mL) towhich a solution of sodium methoxide [prepared from Na_((m)) (18.74 g)in methanol (500 mL)] was added. The mixture was stirred at RT for 3 hand concentrated in vacuo to afford a solid that was dissolved in water(800 mL). The solution was adjusted to approximately pH 9 with additionof a 1N HCl (aq.) solution. The resulting mixture was then extractedwith CH₂Cl₂ (800 mL×3). The combined organic layers were washed withbrine (500 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated.The crude residue was purified by column chromatography (SiO₂: gradientelution 10:1 to 3:1 petroleum ether:ethyl acetate) to afford compoundC3.

Step 4:

To a solution of compound C3 (57 g, 148 mmol) in ethanol (1400 mL) wasadded methyl iodide (26.3 g, 185 mmol). The mixture was heated to 75° C.and stirred overnight. The mixture was then cooled to RT andconcentrated in vacuo. The residue was partitioned between ethyl acetateand a Na₂CO₃(aq.) solution. The mixture was extracted with ethyl acetate(500 mL×3). The combined organic layers were washed with brine, driedover Na₂SO₄, filtered, and concentrated to afford C4 which was usedwithout further purification.

Step 5:

To a solution of compound C4 (100 g, 285 mmol) in CH₂Cl₂ (1000 mL) wereadded Boc₂O (74 g, 343 mmol) and Et₃N (72.2 g, 714 mmol). The mixturewas stirred at RT overnight and then diluted with CH₂Cl₂ (1000 mL). Themixture was then washed with sat. NaHCO₃ (aq.), dried over anhydrousNa₂SO₄, filtered, and concentrated in vacuo. The crude residue waspurified by column chromatography (SiO₂: gradient elution 50:1 to 3:1petroleum ether:hexanes) to afford C5.

Method D

Step 1:

A mixture of C5 (10 g, 20 mmol), Boc₂O (8.7 g, 40 mmol), and DMAP (3.3g, 30 mmol) in DCM (100 mL) was stirred at RT for 6 h, then quenchedwith H₂O. The mixture was extracted with DCM and the combined organiclayers were washed with brine, dried over Na₂SO₄, and concentrated. Theresidue was purified by silica gel chromatography (petroleum ether:EtOAc5:1) to afford D1.

Step 2:

To a solution of D1 (3.0 g, 5.5 mmol) in THF (200 mL) at −78° C. wasadded LiHMDS (1 M solution in THF, 22 mL, 22 mmol). The resultantmixture was then stirred at −78° C. for 1 h, whereupon1-chloro-2-(chloromethoxy)ethane (1.4 g, 11 mmol) was added. Thereaction mixture was allowed to warm to RT and stirred for an additional16 h. The reaction mixture was quenched with a saturated solution ofNH₄Cl(aq.) (10 mL) and the resultant mixture was extracted with EtOAc.The combined extracts were washed with brine, dried over Na₂SO₄, andconcentrated. The residue was purified by silica gel chromatography(petroleum ether:EtOAc 5:1) to afford D2.

Step 3:

To a solution of compound D2 (400 mg, 0.7 mmol) in DCM (2 mL) at 0° C.was added N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (2.2g, 7 mmol), followed by TFA (20 mg, 0.17 mmol) in DCM (0.3 mL). Themixture was stirred at RT for 16 h, then quenched by the addition of aq.NaHCO₃ (10 mL). The resultant mixture was extracted with DCM and thecombined extracts were washed with brine, dried over Na₂SO₄, andconcentrated. The residue was purified by silica gel chromatography(petroleum ether:EtOAc 4:1) to afford D3.

Step 4:

To a solution of compound D3 (180 mg, 0.3 mmol) in EtOH/H₂O (3:1, 20 mL)at 25° C. were added trans-N,N-dimethylcyclohexane-1,2-diamine (14 mg,0.1 mmol), NaN₃ (100 mg, 0.9 mmol), L-ascorbic acid (0.66 M solution inwater, 0.2 mL, 0.13 mmol), and CuSO₄.5H₂O (16.5 mg, 0.07 mmol). Themixture was stirred at 70° C. for 2 h then cooled to RT, and extractedwith EtOAc. The combined extracts were washed with brine, dried overNa₂SO₄, and concentrated. The residue was purified by silica gelchromatography eluting with (PE:EtOAc 3:1) to give D4.

Step 5:

To a solution of D4 (100 mg, 0.18 mmol) in THF/H₂O (2:1, 30 mL) at 25°C. was added PPh₃ (71 mg, 0.27 mmol) and the resultant mixture was thenstirred 80° C. for 16 h. The mixture was then cooled to RT and extractedwith EtOAc. The combined extracts were washed with brine, dried overNa₂SO₄, and concentrated. The residue was purified by silica gelchromatography eluting with petroleum ether:EtOAc (3:1) to afford D5.

Method E

Step 1:

To a solution of D5 (100 mg, 0.19 mmol) in DMF (26 mL) at 25° C. wereadded 5-fluoropyridine-2-carboxylic acid (40 mg, 0.23 mmol), HATU (136mg, 0.36 mmol), and DIEA (46 mg, 0.36 mmol). The reaction mixture wasstirred at 25° C. for 16 h, whereupon it was quenched by water. Themixture was extracted with DCM and the combined extracts were washedwith brine, dried over Na₂SO₄, and concentrated. The residue waspurified by silica gel chromatography (petroleum ether:EtOAc 1:1) toafford E1.

Step 2:

To a solution of E1 (100 mg, 0.17 mmol) in DCM (10 mL) at 0° C. wasadded TFA (1 mL). The mixture was stirred at RT for 2 h, thenconcentrated. The residue was purified by RP-HPLC (column 25×200 mm, 5μm; mobile phases A=water with 0.075% v/v TFA, B=MeCN; gradient 25-55%B, 10 min, 35 mL/min) to give Example 1.

TABLE 1 BACE1 BACE2 LCMS data K_(i) K_(i) m/z t_(R) Ex. Structure (nM)(nM) (M + 1) (min) conditions 1

3.4 4.5 555 2.36 1Method F

Step 1:

To a solution of compound E1 (300 mg, 0.4 mmol) in MeOH (20 mL) at 25°C. was added 10% Pd/C (100 mg). The mixture was stirred at 25° C. underan atmosphere of H₂ (25 psi) for 4 h. The reaction mixture was thenfiltered and the filtrate was concentrated to afford compound F1.

Step 2:

To a solution of compound F1 (100 mg, 0.18 mmol) in DCM (10 mL) at 0° C.was added TFA (1 mL). The mixture was stirred at 25° C. for 2 h,concentrated, and purified by RP-HPLC (column 30×150 mm, 5 μm; mobilephases A=water with 0.075% v/v TFA, B=MeCN; gradient 15-65% B, 10 min,25 mL/min) to give Example 2.

TABLE 2 BACE1 BACE2 LCMS data K_(i) K_(i) m/z t_(R) Ex. Structure (nM)(nM) (M + 1) (min) conditions 2

19.5 30 465 1.99 1Method G

Step 1:

To a solution of compound F1 (140 mg, 0.21 mmol) in DCM (20 mL) at 0° C.were added Et₃N (42 mg, 0.88 mmol) and MeSO₂Cl (100 mg, 0.88 mmol). Themixture was stirred at 0° C. for 2 h, quenched with water, and thenextracted with DCM. The combined extracts were washed with brine, driedover Na₂SO₄, and concentrated. The residue was dissolved in TFA/DCM(10%, 2 mL) and the resultant mixture was stirred for 2 h. The reactionmixture was concentrated and the crude residue was purified by RP-HPLC(column 30×150 mm, 5 μm; mobile phases A=water with 0.075% v/v TFA,B=MeCN; gradient elution 15-55% B, 10 min, 25 mL/min) to give Example 3.

TABLE 3 BACE1 BACE2 LCMS data K_(i) K_(i) m/z t_(R) Ex. Structure (nM)(nM) (M + 1) (min) conditions 3

5 9 543 2.33 1Method H

Step 1:

To a solution of F1 (130 mg, 0.20 mmol) in pyridine (5 mL) at 0° C. wasadded Ac₂O (20 mg, 0.20 mmol). The mixture was stirred at 0° C. for 2 h,then quenched with H₂O, and extracted with EtOAc. The combined extractswere washed with brine, dried over Na₂SO₄, and concentrated. The residuewas dissolved in 10% TFA in DCM (2 mL), stirred for 2 h, andconcentrated. The crude residue was purified by RP-HPLC (column 30×150mm, 5 μm; mobile phases A=water with 0.075% v/v TFA, B=MeCN; gradientelution 15-60% B, 10 min, 25 mL/min) to give Example 4.

TABLE 4 BACE1 BACE2 LCMS data K_(i) K_(i) m/z t_(R) Ex. Structure (nM)(nM) (M + 1) (min) conditions 4

3.7 9 507 2.24 1Method I

Step 1:

To a solution of F1 (80 mg, 0.12 mmol) in DMF (2 mL) at RT were addedcyclopropanecarboxylic acid (12 mg, 0.15 mmol), HATU (91 mg, 0.24 mmol),and DIEA (31 mg, 0.24 mmol). The mixture was stirred at RT for 16 h,then quenched by water and extracted with DCM. The combined extractswere washed with brine, dried over Na₂SO₄, and concentrated. The residuewas dissolved in 10% TFA in DCM (2 mL), stirred for 2 h, andconcentrated. The crude residue was purified by RP-HPLC (column 30×150mm, 5 μm; mobile phases A=water with 0.075% v/v TFA, B=MeCN; gradientelution 15-60% B, 10 min, 25 mL/min) to give Example 5.

The Examples in Table 5 were prepared using a procedure similar to thatdescribed in Method I using the requisite carboxylic acids.

TABLE 5 BACE1 BACE2 LCMS data K_(i) K_(i) m/z t_(R) Ex. Structure (nM)(nM) (M + 1) (min) conditions 5

2.0 3.1 533 2.33 1 6

2.7 5.2 547 3.52 2 7

2.8 5.7 549 2.50 1Method J

As an alternative procedure to Method C step 4, into a 20-L 4-neckedround-bottom flask purged and maintained with an inert atmosphere ofnitrogen was placed a solution of C3 (850 g, 2.21 mol, 1.00 equiv) inCH₃CN (8.5 L). This was followed by addition of trimethyloxoniumtetrafluoroborate (343.7 g, 2.32 mol, 1.05 equiv) in several batches.After the mixture was stirred for 2 h at RT, the mixture was dilutedwith 5 L of ice/water and adjusted to pH 9 with sodium carbonate. Theresulting solution was extracted with dichloromethane (5 L×3). Theorganic layers were combined, washed with brine (2 L), dried overanhydrous sodium sulfate, and concentrated under vacuum. To the residuewas added ethanol (8.5 L) and the mixture was heated at reflux for 2 h.The reaction mixture was cooled and concentrated under vacuum. Theobtained solid was washed with hexane to provide C4.

Method K

As an alternative procedure to Method D step 2, LiHMDS (2.68 L, 2.50equiv) was added to a solution of D1 (590 g, 1.07 mol, 1.00 equiv) intetrahydrofuran (4720 mL) at −78° C. After the mixture was stirred for 1h, to the mixture was added N-methyl-N-methylenemethanaminium iodide(397 g, 6.83 mol, 2.00 equiv) in several portions. The resulting mixturewas stirred for 4 h at −78° C., followed by addition of iodomethane (761g, 5.36 mol, 5.00 equiv) at 0° C. The resulting solution was stirredovernight at RT. To the mixture was added aq. NaHCO₃ (3 L) and theresultant mixture was stirred for an additional 1 h at RT. The resultingmixture was extracted with ethyl acetate (5 L×2). The organic layerswere combined, washed with brine 1 L), dried over anhydrous sodiumsulfate, and concentrated under vacuum. The residue was applied onto asilica gel column and eluted with ethyl acetate/petroleum ether (1:20)to provide D2.

Method L

Into a 5000-mL 4-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen were added D4 (140 g, 250.61 mmol, 1.00equiv), tetrahydrofuran (1050 mL), and water (350 mL). The resultantmixture was cooled to 0° C. To the mixture was added a solution oftrimethylphosphine in toluene (376 mL, 1.50 equiv) dropwise withstirring at 0° C. The reaction mixture was then allowed to warm to RTand stir for 4 hours. After that time, the mixture was extracted withethyl acetate (1 L×3). The organic layers were combined, washed withbrine (500 mL), dried over anhydrous sodium sulfate, and concentratedunder vacuum. The residue was applied onto a silica gel column andeluted with ethyl acetate/petroleum ether (gradient 1:6-1:5) to affordL1 along with L2 that required further purification. The residuecontaining L2 was repurified by flash chromatography using the followingconditions: column, C18 silica; gradient elution 40-95% MeCN in water;Detector, UV 210 nm.) to afford L2. Analytical data for L1: m/z 532[M+H⁺] Analytical data for L2: m/z 532 [M+H].

Method M

Step 1:

To a solution of L2 (500 mg, 0.941 mmol), 5-methoxy-2-picolinic acid(172 mg, 1.12 mmol), and DIEA (364.1 mg, 2.82 mmol) in tetrahydrofuran(7.5 mL) at 0° C. was added a solution of T3P (50% in EtOAc, 897.7 mg,1.41 mmol). The reaction mixture was stirred for 5 h at RT. After thattime, to the reaction was added cold water and the resultant reactionmixture was extracted with EtOAc. The combined organic layers werewashed with brine, dried over anhydrous Na₂SO₄, and concentrated. Thecrude residue was purified by column chromatography (SiO₂) eluting with50% EtOAc in hexanes to afford M1. m/z: 667.0 (M+H)⁺,

Step 2:

To a solution of M1 (200 mg, 0.3 mmol) in EtOAc (10 mL) was added 10%Pd/C (40 mg) followed by 2 drops of acetic acid. The reaction mixturewas degassed and then stirred under an atmosphere of hydrogen (balloon)for 4 h. The reaction mixture was filtered through a celite bed and thefilter bed was washed with 1:1 mixture of dichloromethane and methanol.The combined filtrates were concentrated and purified by columnchromatography (SiO₂) eluting with 10% methanol in dichloromethane toyield M2. m/z: 577.0 (M+H⁺).

TABLE 6 Intermediates M3-M5 were prepared using procedures similar tothose described in Scheme M from either L1 or L2 and the requisitecarboxylic acids.

M3

M4

M5Method N

Parallel preparation of Examples 8-17: To a set of vials each containinga solution of M2 (25 mg, 0.043 mmol) in MeOH (1 mL) was added therequisite aldehyde (0.052 mmol) and acetic acid (0.010 mL, 0.17 mmol).The solutions were shaken at RT for 10 min. To each of the vials wasthen added MP-cyanoborohydride (Biotage) (48 mg, 0.10 mmol) and themixtures were shaken at RT overnight. The mixtures were then filteredand the solvent was removed in vacuo. To each vial was added TFA (0.5mL). The mixtures were shaken at RT for 3 hours. The solvent was thenremoved in vacuo. Each crude residue was redissolved in 1 mL of DMSO andfiltered. The residues containing Examples 8-16 were purified by masstriggered HPLC using the following conditions: [Waters XBridge C18column, 5 μm, 19×100 mm, gradient ranges from 10% initial to 60-70% MeCN(0.1% NH₄OH) in water (0.1% NH₄OH) 50 mL/min, 8-15 min run time] toprovide Examples 8-16. The crude residue containing Example 17 waspurified by mass triggered HPLC using the following conditions: [column:Waters Sunfire C18, 5 μm, 19×100 mm; solvent: gradient range 10% initialto 40% final MeCN (0.1% formic acid) in water (0.1% formic acid) 50mL/min; 8 min run time] to afford Example 17.

TABLE 7 BACE1 BACE2 LCMS data K_(i) K_(i) m/z t_(R) Ex. Structure (nM)(nM) (M + 1) (min) conditions  8

3 13 574.16 0.75 3  9

1 2 561.22 0.73 3 10

2 13 568.21 0.72 3 11

2 12 568.21 0.72 3 12

2 7 531.21 0.71 3 13

1 1 573.18 0.99 3 14

3 9 558.1  (M + 1)9 0.79 3 15

4 17 569.2  0.82 3 16

4 26 571.22 0.67 3 17

4 21 575.24 0.73 3Method O

Parallel preparation of Examples 18-28: These examples were preparedfrom M3 and the requisite aldehydes using a procedure similar to thatdescribed in Method N. The crude residues were purified by masstriggered HPLC using the following conditions: [column: Waters XBridgeC18, 5 μm, 19×100 mm; solvent: gradient range 20-35% initial to 55-70%final MeCN (0.1% NH₄OH) in water (0.1% NH₄OH) 25 mL/min; 8 min run time]to afford Examples 18-28.

TABLE 8 BACE1 BACE2 LCMS data K_(i) K_(i) m/z t_(R) Ex. Structure (nM)(nM) (M + 1) (min) conditions 18

47 158 558.19 0.70 3 19

20 70 574.16 0.73 3 20

51 188 561.22 0.73 3 21

91 201 575.24 0.72 3 22

26 79 568.21 0.71 3 23

30 142 568.21 0.71 3 24

34 128 531.21 0.70 3 25

15 52 573.18 1.02 3 26

51 329 569.2  0.84 3 27

54 388 571.22 0.64 3 28

28 237 558.19 0.79 3Method P

Parallel preparation of Examples 29-41: These examples were preparedfrom M4 and the requisite aldehyde using a procedure similar to thatdescribed in Method N. The crude residues were purified by masstriggered HPLC using the following conditions: [column: Waters XBridgeC18, 5 μm, 19×100 mm; solvent: gradient range 15-30% initial to 50-70%final MeCN (0.1% NH₄OH) in water (0.1% NH₄OH) 25 mL/min; 8 min run time]to afford Examples 29-41.

TABLE 9 BACE1 BACE2 LCMS data K_(i) K_(i) m/z t_(R) Ex. Structure (nM)(nM) (M + 1) (min) conditions 29

8 9 556.19 0.70 3 30

4 5 546.17 0.78 3 31

2 5 519.19 0.70 3 32

1 1 549.2  0.71 3 33

3 5 562.14 0.73 3 34

6 10 563.22 0.72 3 35

2 6 556.19 0.70 3 36

1 1 561.16 0.98 3 37

2 5 546.17 0.70 3 38

4 7 557.18 0.80 3 39

2 3 521.21 0.74 3 40

4 10 559.2  0.65 3 41

3 6 556.19 0.71 3Method Q

Parallel preparation of Examples 42-54: These examples were preparedfrom M5 and the requisite aldehydes using a procedure similar to thatdescribed in Method N. The crude residues containing examples 42-53 werepurified by mass triggered HPLC using the following conditions: [column:Waters Sunfire C18, 5 μm, 19×100 mm; solvent: gradient range 8-15%initial to 35-50% final MeCN (0.1% formic acid) in water (0.1% formicacid) 25 mL/min; 8 min run time] to afford Examples 42-53. The cruderesidue containing Example 54 was purified using the followingconditions: [column: Waters XBridge C18, 5 μm, 19×100 mm; solvent:gradient from 20% initial to 55% final MeCN (0.1% NH₄OH) in water (0.1%NH₄OH) 25 mL/min; 8 min run time] to afford Example 54.

TABLE 10 BACE1 BACE2 LCMS data K_(i) K_(i) m/z t_(R) Ex. Structure (nM)(nM) (M + 1) (min) conditions 42

 32  25 562.14 0.71 3 43

119  72 549.2  0.71 3 44

120  52 563.22 0.70 3 45

 33  23 556.19 0.69 3 46

 54  40 556.19 0.69 3 47

 58  51 519.19 0.68 3 48

 22  14 561.16 1.01 3 49

 33  21 546.17 0.68 3 50

 70  77 557.18 0.82 3 51

151 184 559.2  0.62 3 52

 73  61 521.21 0.73 3 53

 84  61 556.19 0.69 3 54

 54  74 546.17 0.77 3Method R

Parallel preparation of Examples 55-62: To a set of vials eachcontaining a solution of M2 (30 mg, 0.052 mmol) in DCM (1 mL) was addediPr₂NEt (0.027 mL, 0.16 mmol) followed by the requisite sulfonylchlorides (0.10 mmol). The solutions were shaken at RT overnight. Afterthat time, to each of the vials was added TFA (0.5 mL). The mixtureswere shaken at RT for 3 h and the solvent was then removed in vacuo.Each crude residue was redissolved in 1 mL of DMSO and filtered. Thecrude residues were purified by mass triggered HPLC using the followingconditions: [Waters XBridge C18 column, 5 μm, 19×100 mm, gradient rangesfrom 17-35% initial to 55-70% MeCN (0.1% NH₄OH) in water (0.1% NH₄OH) 25mL/min, 8 min run time] to provide Examples 55-62.

TABLE 11 BACE1 BACE2 LCMS data K_(i) K_(i) m/z t_(R) Ex. Structure (nM)(nM) (M + 1) (min) conditions 55

3 10 555.14 0.85 3 56

1  6 569.16 0.90 3 57

1  5 597.19 1.04 3 58

3 20 635.15 1.06 3 59

3 16 617.16 1.03 3 60

1  4 581.16 0.93 3 61

6 38 621.16 0.83 3 62

3 19 625.18 0.94 3Method S

Parallel preparation of Examples 63-72: These examples were preparedfrom M3 and the requisite sulfonyl chlorides using a procedure similarto that described in Method R. The crude residues were purified by masstriggered HPLC using the following conditions: [column: Waters XBridgeC18, 5 μm, 19×100 mm; solvent: gradient range 12-27% initial to 42-57%final MeCN (0.1% NH₄OH) in water (0.1% NH₄OH) 25 mL/min; 8 min run time]to afford Examples 63-71. Example 72 was repurified by mass triggeredHPLC using the following conditions: [column: Waters Sunfire C18, 5 μm,19×100 mm; solvent: gradient of 10% initial to 32% final MeCN (0.1%formic acid) in water (0.1% formic acid) 50 mL/min; 8 min run time] toafford Example 72.

TABLE 12 BACE1 BACE2 LCMS data K_(i) K_(i) m/z t_(R) Ex. Structure (nM)(nM) (M + 1) (min) conditions 63

12  24 617.16 1.02 3 64

40 140 581.16 0.91 3 65

29  68 621.16 0.81 3 66

32  87 625.18 0.93 3 67

20  40 607.15 0.82 3 68

35 205 555.14 0.83 3 69

33 157 569.16 0.89 3 70

37 100 597.19 1.02 3 71

24  30 635.15 1.04 3 72

28  99 623.13 0.99 3Method T

Parallel preparation of Examples 73-84: These examples were preparedfrom M4 and the requisite sulfonyl chlorides using a procedure similarto that described in Method R. The crude residues were purified by masstriggered HPLC using the following conditions: [column: Waters SunfireC18, 5 μm, 19×100 mm; solvent: gradient range 8-20% initial to 40-55%final MeCN (0.1% TFA) in water (0.1% TFA) 25 mL/min; 8-12 min run time]to afford Examples 73-83. Example 84 was repurified by mass triggeredHPLC using the following conditions: [column: Waters XBridge C18, 5 μm,19×100 mm; solvent: gradient from 30% initial to 65% final MeCN (0.1%NH₄OH) in water (0.1% NH₄OH) 25 mL/min; 8 min run time] to affordExample 84.

TABLE 13 BACE1 BACE2 LCMS data K_(i) K_(i) t_(R) Ex. Structure (nM) (nM)m/z (min) conditions 73

3 10 623.13 1.07 3 74

2  4 611.11 1.02 3 75

4  7 543.12 0.85 3 76

2  4 557.14 0.90 3 77

2  3 585.17 1.05 3 78

2  7 605.14 1.04 3 79

1  2 569.14 0.93 3 80

2  5 620.15 0.75 3 81

8 24 609.14 0.83 3 82

4 10 613.16 0.95 3 83

5 11 595.13 0.83 3 84

2  2 597.17 1.03 3Method U

Parallel preparation of Examples 85-95: These examples were preparedfrom M5 and the requisite sulfonyl chlorides using a procedure similarto that described in Method R. The crude residues were purified by masstriggered HPLC using the following conditions: [column: Waters SunfireC18, 5 μm, 19×100 mm; solvent: gradient range 10-13% initial to 32-43%final MeCN (0.1% TFA) in water (0.1% TFA) 25 mL/min; 9-12 min run time]to afford Examples 85-94. Example 95 was repurified by mass triggeredHPLC using the following conditions: [column: Waters XBridge C18, 5 μm,19×100 mm; solvent: gradient from 24% initial to 54% final MeCN (0.1%NH₄OH) in water (0.1% NH₄OH) 25 mL/min; 8 min run time] to affordExample 95.

TABLE 14 BACE1 BACE2 LCMS data K_(i) K_(i) m/z t_(R) Ex. Structure (nM)(nM) (M + 1) (min) conditions 85

41 37 86

42 20 623.13 1.07 3 87

15  5 611.11 1.02 3 88

34 54 543.12 0.85 3 89

45 41 557.14 0.90 3 90

48 29 585.17 1.05 3 91

16  6 605.14 1.04 3 92

41 29 569.14 0.93 3 93

28 20 620.15 0.75 3 94

37 19 609.14 0.83 3 95

25  6 613.16 0.95 3Method V:

Step 1:

Amine L2 was converted to V1 using a procedure similar to that describedin Scheme M step 1. m/z=604.2 (M+H⁺).

Step 2:

To the solution of V1 (110 mg, 0.331 mmol) in dichloromethane (5 mL) at0° C. was added 4M HCl in dioxane (10 mL) slowly. The reaction mixturewas allowed to warm to RT and stir for 2 h. The reaction mixture wasconcentrated and the residue was purified by preparative reverse phaseHPLC (Column: Symmetry Prep C18 (19×300 mm) 7 μm; column temp: ambient;mobile phase: A: 0.1% TFA in water, B: 100% acetonitrile; Gradient: From0 to 20 min 90:10 to 50:50 (A:B), from 21-25 min 50:50 to 40:60 (A:B),from 25 to 26 mins 40:60 to 0:100(A:B), from 26-30 mins 0:100(A:B); flowrate: 15 mL/min; UV detection: 215 nm) to afford Example 96.

Step 3:

To a solution of V1 (200 mg, 0.331 mmol) in 1,2-dichloroethane (10 mL)at 0° C. was added 1-chloroethyl chloroformate (140 mg, 0.991 mmol)slowly. The reaction mixture was allowed to warm to RT and then heatedat 90° C. for 3 h. Reaction mixture was then concentrated. The residuewas taken in methanol and heated at 70° C. for 4 h. After that time, thereaction mixture was concentrated and the residue was purified bypreparative reverse phase HPLC (see HPLC conditions described in MethodV step 2) to afford Example 97.

TABLE 15 BACE1 BACE2 LCMS data K_(i) K_(i) m/z t_(R) Ex. Structure (nM)(nM) (M + 1) (min) conditions 96

 22  25 504.2 3.16 4 97

1037 782 414.2 1.81 5LCMS Conditions:

Conditions 1:

Column: Agilent TC-C₁₈ (2.1×50 mm) 5 μm; Mobile phase: A: 0.0375%Trifluoroacetic acid in water, B: 0.01875% Trifluoroacetic acid inacetonitrile; Gradient: 99:1 (A:B) for 0.4 min, 99:1 to 10:90 (A:B) over3 min, 10:90 to 0:100 (A:B) over 0.6 min; Flow rate: 0.8 mL/min; UVdetection: 254 and 220 nm; Mass spectrometer: Agilent 6110 quadrupole.

Conditions 2:

Column: Agilent TC-C₁₈ (2.1×50 mm) 5 μm; Mobile phase: A: 0.0375%Trifluoroacetic acid in water, B: 0.01875% Trifluoroacetic acid inacetonitrile; Gradient: 100:0 (A:B) for 0.4 min, 100:0 to 20:80 (A:B)over 3 min, 20:80 to 0:100 (A:B) over 0.6 min; Flow rate: 0.6 mL/min; UVdetection: 254 and 220 nm; Mass spectrometer: Agilent 6110 quadrupole.

Conditions 3:

Waters Acquity UPLC/MS, Electrospray positive ion mode; Column: WatersAcquity UPLC BEH C18, 2.1×50 mm, 1.7 micron; Gradient elution 5:95 to100:0 MeCN (0.1% NH₄OH): water (0.1% NH₄OH) over 1.4 min 0.8 mL/min; UV:220 nm.

Conditions 4:

Column: ZORBAX XDB-C18 (50×4.6 mm) 5.0 micron; column temp: ambient;mobile phase; A: 10 mM ammonium acetate, B: 100% acetonitrile; gradient:0 to 3 min 90:10 to 5:95 (A:B), from 3 to 5 mins 5:95 (A:B), from 5 to5.5 mins 5:95 to 90:10 (A:B) Flow rate: 1.2 mL/min; UV detection: 215nm; mass spectrometer: Agilent 6130(Single)quadruple.

Conditions 5:

Column: XBRIDGE C18 (50×4.6 mm) 5.0 micron; column temp: ambient; mobilephase: A:10 mM ammonium acetate in water, B: 100% acetonitrile;gradient: 0 to 3 min 95:5 to 5:95 (A:B), from 3 to 5 min 5:95 (A:B);flow rate: 1.5 mL/min; UV detection: 215 nm; mass spectrometer: Agilent6130(Single)quadrupole.

Assays

Protocols that used to determine the recited potency values for thecompounds of the invention are described below.

BACE1 HTRF FRET Assay

Reagents:

Na⁺-Acetate pH 5.0; 1% Brij-35; Glycerol; Dimethyl Sulfoxide (DMSO);Recombinant human soluble BACE1 catalytic domain (>95% pure); APPSwedish mutant peptide substrate (QSY7-APP^(swe)-Eu):QSY7-EISEVNLDAEFC-Europium-amide.

A homogeneous time-resolved FRET assay can be used to determine IC₅₀values for inhibitors of the soluble human BACE1 catalytic domain. Thisassay monitors the increase of 620 nm fluorescence that resulted fromBACE1 cleavage of an APPswedish APP^(swe) mutant peptide FRET substrate(QSY7-EISEVNLDAEFC-Europium-amide). This substrate contains anN-terminal QSY7 moiety that serves as a quencher of the C-terminalEuropium fluorophore (620 nm Em). In the absence of enzyme activity, 620nm fluorescence is low in the assay and increased linearly over 3 hoursin the presence of uninhibited BACE1 enzyme. Inhibition of BACE cleavageof the QSY7-APP^(swe)-Eu substrate by inhibitors is manifested as asuppression of 620 nm fluorescence.

Varying concentrations of inhibitors at 3× the final desiredconcentration in a volume of 10 ul are preincubated with purified humanBACE1 catalytic domain (3 nM in 10 μl) for 30 minutes at 30° C. inreaction buffer containing 20 mM Na-Acetate pH 5.0, 10% glycerol, 0.1%Brij-35 and 7.5% DSMO. Reactions are initiated by addition of 10 μl of600 nM QSY7-APP^(swe)-Eu substrate (200 nM final) to give a finalreaction volume of 30 μl in a 384 well Nunc HTRF plate. The reactionsare incubated at 30° C. for 1.5 hours. The 620 nm fluorescence is thenread on a Rubystar HTRF plate reader (BMG Labtechnologies) using a 50millisecond delay followed by a 400 millisecond acquisition time window.Inhibitor IC₅₀ values are derived from non-linear regression analysis ofconcentration response curves. K_(i) values are then calculated fromIC₅₀ values using the Cheng-Prusoff equation using a previouslydetermined μm value of 8 μM for the QSY7-APP^(swe)-Eu substrate atBACE1.

BACE-2 Assay

Inhibitor IC₅₀'s at purified human autoBACE-2 are determined in atime-resolved endpoint proteolysis assay that measures hydrolysis of theQSY7-EISEVNLDAEFC-Eu-amide FRET peptide substrate (BACE-HTRF assay).BACE-mediated hydrolysis of this peptide results in an increase inrelative fluorescence (RFU) at 620 nm after excitation with 320 nmlight. Inhibitor compounds, prepared at 3× the desired finalconcentration in 1×BACE assay buffer (20 mM sodium acetate pH 5.0, 10%glycerol, 0.1% Brij-35) supplemented with 7.5% DMSO are pre-incubatedwith an equal volume of autoBACE-2 enzyme diluted in 1×BACE assay buffer(final enzyme concentration 1 nM) in black 384-well NUNC plates for 30minutes at 30° C. The assay is initiated by addition of an equal volumeof the QSY7-EISEVNLDAEFC-Eu-amide substrate (200 nM final concentration,K_(m)=8 μM for 4 μM for autoBACE-2) prepared in 1×BACE assay buffersupplemented with 7.5% DMSO and incubated for 90 minutes at 30° C. DMSOis present at 5% final concentration in the assay. Following laserexcitation of sample wells at 320 nm, the fluorescence signal at 620 nmis collected for 400 ms following a 50 μs delay on a RUBYstar HTRF platereader (BMG Labtechnologies). Raw RFU data is normalized to maximum (1.0nM BACE/DMSO) and minimum (no enzyme/DMSO) RFU values. IC_(50s) aredetermined by nonlinear regression analysis (sigmoidal dose response,variable slope) of percent inhibition data with minimum and maximumvalues set to 0 and 100 percent respectively. Similar IC_(50s) areobtained when using raw RFU data. The K_(i) values are calculated fromthe IC₅₀ using the Cheng-Prusoff equation.

What is claimed is:
 1. A compound, or a pharmaceutically acceptable saltthereof, said compound having the structural Formula (I):

or a tautomer thereof having the structural Formula (I′):

or pharmaceutically acceptable salt of said tautomer, wherein: R¹ isselected from the group consisting of H, alkyl, heteroalkyl, cycloalkyl,and -alkyl-cycloalkyl, wherein each said alkyl, heteroalkyl, cycloalkyl,and -alkyl-cycloalkyl is optionally substituted with one or morehalogen; ring C is a moiety selected from the group consisting of

each R² is independently selected from the group consisting of H,-alkyl-OH, alkyl, heteroalkyl, and cycloalkyl wherein each said alkyl,heteroalkyl, and cycloalkyl of R² is optionally substituted withhalogen; each R³ is independently selected from the group consisting ofH, halogen, -alkyl-OH, alkyl, heteroalkyl, alkoxy, and cycloalkyl,wherein each said alkyl, heteroalkyl, alkoxy, and cycloalkyl of R³ isoptionally substituted with halogen; R^(N) is selected from the groupconsisting of: H, —C(O)R^(6N), —C(O)OR^(6N), —C(O)N(R^(6N))₂,—S(O)₂R^(6N), —S(O)₂N(R^(6N))₂, alkyl, heteroalkyl, cycloalkyl,-alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkyl, aryl,-alkyl-aryl, heteroaryl, and -alkyl-heteroaryl, wherein said alkyl,heteroalkyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl,-alkyl-heterocycloalkyl, aryl, -alkyl-aryl, heteroaryl, and-alkyl-heteroaryl, of R^(N) are each optionally independentlyunsubstituted or substituted with one or more groups independentlyselected from R⁹; R⁴ is selected from the group consisting of H, alkyl,heteroalkyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and-alkyl-heterocycloalkyl, wherein each said alkyl, heteroalkyl,cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and-alkyl-heterocycloalkyl is optionally substituted with one or morehalogen; ring A is selected from the group consisting of aryl andheteroaryl; m is 0 or more; each R^(A) (when present) is independentlyselected from the group consisting of: halogen, oxo, —OH, —CN, —SF₅,—OSF₅, —Si(R^(5A))₃, —N(R^(6A))₂, —OR^(6A), —SR^(6A), alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, -alkyl-cycloalkyl,heterocycloalkyl, and -alkyl-heterocycloalkyl, wherein said alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, -alkyl-cycloalkyl,heterocycloalkyl, and -alkyl-heterocycloalkyl of R^(A) are eachoptionally independently unsubstituted or substituted with one or moregroups independently selected from R⁸; -L₁- is a divalent moietyselected from the group consisting of —NHC(O)— and —C(O)NH—; R^(L) isselected from the group consisting of alkyl and heteroalkyl, whereinsaid alkyl and heteroalkyl of R^(L) are each optionally unsubstituted orsubstituted with one or more halogen; or, alternatively, R^(L) is amoiety having the formula

wherein q is 0 or 1; -L_(B)- (when present) is a divalent moietyselected from the group consisting of lower alkyl and lower heteroalkyl,wherein each said lower alkyl and lower heteroalkyl is optionallysubstituted with one or more halogen; ring B is selected from the groupconsisting of aryl, heteroaryl, cycloalkyl, cycloalkenyl,heterocycloalkyl, and heterocycloalkenyl; p is 0 or more; and each R^(B)(when present) is independently selected from the group consisting of:halogen, oxo, —OH, —CN, —SF₅, —OSF₅, —Si(R^(5B))₃, —N(R^(6B))₂,—NR^(7B)C(O)R^(6B), —NR^(7B)S(O)₂R^(6B), —NR^(7B)S(O)₂N(R^(6B))₂,—NR^(7B)C(O)N(R^(6B))₂, —NR^(7B)C(O)OR^(6B), —C(O)R^(6B), —C(O)OR^(6B),—C(O)N(R^(6B))₂, —S(O)R^(6B), —S(O)₂R^(6B), —S(O)₂N(R^(6B))₂, —OR^(6B),—SR^(6B), alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl,-alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkyl, aryl,-alkyl-aryl, heteroaryl, and -alkyl-heteroaryl, wherein said alkyl,heteroalkyl, alkenyl, alkynyl, cycloalkyl, -alkyl-cycloalkyl,heterocycloalkyl, -alkyl-heterocycloalkyl, aryl, -alkyl-aryl,heteroaryl, and -alkyl-heteroaryl, of R^(B) are each optionallyindependently unsubstituted or substituted with one or more groupsindependently selected from R⁹; each R^(5A) and R^(5B) (when present) isindependently selected from the group consisting of alkyl, heteroalkyl,cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl,-alkyl-heterocycloalkyl, wherein each said alkyl, heteroalkyl,cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkylof R^(5A) and R^(5B) is unsubstituted or substituted with one or morehalogen; each R^(6N) and R^(6A) (when present) is independently selectedfrom the group consisting of H, alkyl, -alkyl-OH, alkenyl, alkynyl,heteroalkyl, -heteroalkyl-OH, cycloalkyl, -alkyl-cycloalkyl,heterocycloalkyl, -alkyl-heterocycloalkyl, aryl, heteroaryl,-alkyl-aryl, and -alkyl-heteroaryl, wherein each said alkyl, -alkyl-OH,alkenyl, alkynyl, heteroalkyl, -heteroalkyl-OH, cycloalkyl,-alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkyl, aryl,-alkyl-aryl, heteroaryl, and -alkyl-heteroaryl of R^(6N) and R^(6A) isunsubstituted or substituted with one or more groups independentlyselected from halogen, alkyl, cycloalkyl, heteroalkyl, haloalkyl,alkoxy, heteroalkoxy, and haloalkoxy; each R^(6B) (when present) isindependently selected from the group consisting of H, alkyl, -alkyl-OH,alkenyl, alkynyl, heteroalkyl, -heteroalkyl-OH, cycloalkyl,-alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkyl, aryl,-alkyl-aryl, heteroaryl, and -alkyl-heteroaryl, wherein each said alkyl,-alkyl-OH, alkenyl, alkynyl, heteroalkyl, -heteroalkyl-OH, cycloalkyl,-alkyl-cycloalkyl, heterocycloalkyl, -alkyl-heterocycloalkyl, aryl,-alkyl-aryl, heteroaryl, and -alkyl-heteroaryl of R^(6B) isunsubstituted or substituted with one or more groups independentlyselected from halogen, alkyl, cycloalkyl, heteroalkyl, haloalkyl,alkoxy, heteroalkoxy, and haloalkoxy; each R^(7B) (when present) isindependently selected from the group consisting of H, alkyl,heteroalkyl, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and-alkyl-heterocycloalkyl, wherein each said alkyl, heteroalkyl,-heteroalkyl-OH, cycloalkyl, -alkyl-cycloalkyl, heterocycloalkyl, and-alkyl-heterocycloalkyl of R^(7B) is unsubstituted or substituted withone or more halogen; each R⁸ (when present) is independently selectedfrom the group consisting of halogen, lower alkyl, lower heteroalkyl,lower alkoxy, lower cycloalkyl, and lower heterocycloalkyl, wherein eachsaid lower alkyl, lower heteroalkyl, lower alkoxy, lower cycloalkyl, andlower heterocycloalkyl of R⁸ is optionally substituted with halogen; andeach R⁹ (when present) is independently selected from the groupconsisting of halogen, —OH, —CN, —SF₅, —OSF₅, alkyl, -alkyl-OH,heteroalkyl, -heteroalkyl-OH, alkoxy, —O-heteroalkyl, cycloalkyl,-alkyl-cycloalkyl, —O-cycloalkyl, —O-alkyl-cycloalkyl,-heterocycloalkyl, -alkyl-heterocycloalkyl, —O-heterocycloalkyl and—O-alkyl-heterocycloalkyl, wherein each said alkyl, -alkyl-OH,heteroalkyl, -heteroalkyl-OH, alkoxy, —O-heteroalkyl, cycloalkyl,-alkyl-cycloalkyl, —O-cycloalkyl, —O-alkyl-cycloalkyl,-heterocycloalkyl, -alkyl-heterocycloalkyl, —O-heterocycloalkyl and—O-alkyl-heterocycloalkyl are optionally substituted with one or morehalogen.
 2. A compound of claim 1, or a tautomer thereof, or apharmaceutically acceptable salt of said compound or said tautomer,wherein: ring C is:

wherein each R^(N) group is selected from the group consisting of H,—C(O) CH₃, —C(O)CH₂CH₃, —C(O)CH₂CH(CH₃)₂, —C(O)-cyclopropyl,—C(O)—CH₂-cyclopropyl, —C(O)N(CH₃)₂, —C(O)NHCH₃, —S(O)₂CH₃,—S(O)₂CH₂CH₃, —S(O)₂CH₂CF₃, —S(O)₂CH₂CH(CH₃)₂, —S(O)₂-phenyl,—S(O)₂CH₂-pyridyl, —S(O)₂-cyclopentyl, —S(O)₂-cyclopropyl,—S(O)₂-imidazolyl, —S(O)₂—CH₂-tetrahydrofuranyl, —S(O)₂-pyrazolyl,—S(O)₂N(CH₃)₂, —S(O)₂NHCH₃, methyl, ethyl, propyl, cyclopropyl, butyl,—CH₂-cyclopropyl, benzyl, —CH₂OCH₃, —CH₂OCH₂CH₃, phenyl, pyridyl,pyrimidinyl, pyrazinyl, oxadiazolyl, isoxazolyl, oxazolyl, and pyrrolyl,—CH₂-thiazolyl, —CH₂— oxazoyl, —CH₂-pyridyl, —CH₂-pyrimidinyl,—CH₂-pyrazinyl, —CH₂-pyrazolyl, —CH₂-cyclobutyl, —CH₂-cyclopropyl,—CH₂-tetrahydrofuranyl, wherein said benzyl, cyclobutyl, phenyl,pyridyl, oxadiazolyl, imidazolyl, isoxazolyl, oxazolyl, and pyrrolyl areeach optionally unsubstituted or substituted with fluorine, chlorine,methyl, —CN, —CF₃, CHF₂, and —OMe; R¹ is methyl; each R² is H; each R³is independently selected from the group consisting of H and fluorine;and R⁴ is selected from the group consisting of methyl and —CHF₂.
 3. Acompound of claim 2, or a tautomer thereof, or a pharmaceuticallyacceptable salt of said compound or said tautomer, wherein: ring A isselected from the group consisting of phenyl, pyridazinyl, pyridyl,pyrimidinyl, pyrazinyl, triazinyl, and tetrazinyl; m is 0, 1, or 2; andeach R^(A) (when present) is independently selected from the groupconsisting of halogen, oxo, —CN, —SF₅, —NHCH₃, —N(CH₃)₂, —OCH₃,—OCH₂CH₃, —O-cyclopropyl, —O—CH₂-cyclopropyl, —CH₂OCH₃, —S(CH₃), methyl,ethyl, cyclopropyl, —CH₂-cyclopropyl, —CF₃, —CHF₂, —CH₂F, —OCF₃, and—OCHF₂.
 4. A compound of claim 3, or a tautomer thereof, or apharmaceutically acceptable salt of said compound or said tautomer,wherein: R^(L) is selected from the group consisting of methyl, ethyl,propyl, butyl, —CF₃, —CHF₂, —CH₂CF₃, —CF₂CH₃, —CH₂OCH₃, —CH₂OCH₂CH₃,—CH₂CH₂OCH₃, —CH₂SCH₃, —CH₂SCH₂CH₃, —CH₂CH₂SCH₃, —CH₂N(CH₃)₂, —CH₂NHCH₃,—CH₂CH₂N(CH₃)₂, —CH₂OCF₃, and —CH₂OCHF₂.
 5. A compound of claim 3, or atautomer thereof, or a pharmaceutically acceptable salt of said compoundor said tautomer, wherein: R^(L) is a moiety having the formula

q is 0 or 1; -L_(B)- (when present) is a divalent moiety selected fromthe group consisting of —CH₂—, —CH₂CH₂—, —CH₂O—, and —CF₂O—; ring B isselected from the group consisting of azetidinyl, benzimidazolyl,benzoisothiazolyl, benzoisoxazoyl, benzothiazolyl, benzoxazoyl,cyclobutyl, cyclohexyl, cyclopentyl, cyclopropyl, dihydroindenyl,dihydrooxazolyl, furanyl, imidazolyl, imidazopyridinyl,imidazopyrimidinyl, indenyl, indolyl, isothiazolyl, isoxazolyl,morpholinyl, oxadiazolyl, oxazolyl, oxetanyl, phenyl, piperazinyl,piperidinyl, pyrazinyl, pyrazolyl, pyrazolopyridinyl,pyrazolopyrimidinyl, pyridazinyl, pyridyl, pyrimidinyl,pyrazolopyridinyl, pyrrolidinyl, pyrrolyl, pyrrolopyridinyl,pyrrolopyrimidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrazolyl,thiadiazolyl, thiazolyl, thienyl, thienylpyridine, thiomorpholinyl,thiomorpholinyl dioxide, and triazolyl; p is 0 or more; and each R^(B)group (when present) is independently selected from the group consistingof halogen, oxo, —OH, —CN, —SF₅, —NH₂, —NH(CH₃), —N(CH₃)₂, —NHC(O)CH₃,—N(CH₃)C(O)CH₃, —NHS(O)₂CH₃, —N(CH₃)S(O)₂CH₃, —C(O)OCH₃, —C(O)OCH₂CH₃,—C(O)N(CH₃)₂, —C(O)NHCH₃, —S(O)₂CH₃, —S(O)₂N(CH₃)₂, —S(O)₂NHCH₃, —OCH₃,—OCH₂CH₃, —O-cyclopropyl, —O—CH₂-cyclopropyl, —OCH₂—C≡C—H,—OCH₂—C≡C—CH₃, —S(CH₃), methyl, ethyl, propyl, cyclopropyl,—CH₂-cyclopropyl, —CH₂OCH₃, —CH₂OCH₂CH₃, —C≡CH, —C≡C—CH₃, —CF₃, —CHF₂,—CH₂F, —OCF₃, —OCH₂CF₃, —OCHF₂, —OCH₂F, —OCH₂CH₂F, phenyl, pyridyl,oxadiazoyl, isoxazoyl, oxazoyl, and pyrrolyl, wherein each said phenyl,pyridyl, oxadiazoyl, isoxazoyl, oxazoyl, and pyrrolyl is optionallysubstituted with from 1 to 3 substituents independently selected fromthe group consisting of F, Cl, CN, —CH₃, —OCH₃, and —CF₃.
 6. A compoundof claim 5, or a tautomer thereof, or a pharmaceutically acceptable saltof said compound or said tautomer, wherein: R^(L) is a moiety having theformula

q is 0 or 1; -L_(B)- (when present) is a divalent moiety selected fromthe group consisting of —CH₂—, —CF₂—, —CH₂CH₂—, —CH₂O—, and —CF₂O—; ringB is selected from the group consisting of isoxazoyl, oxadiazoyl,oxazolyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, and pyrazolyl; p is0 or more; and each R^(B) group (when present) is independently selectedfrom the group consisting of fluoro, chloro, —CN, —S(O)₂CH₃, —OCH₃,—O-cyclopropyl, —O—CH₂-cyclopropyl, —OCH₂—C≡C—H, —OCH₂—C≡C—CH₃, methyl,cyclopropyl, —CH₂-cyclopropyl, —CH₂OCH₃, —C≡C—CH₃, —CF₃, —CHF₂, —CH₂F,—OCF₃, —OCHF₂, —OCH₂F, and —OCH₂CH₂F.
 7. A compound of claim 6, or atautomer thereof, or a pharmaceutically acceptable salt of said compoundor said tautomer, wherein: q is 0; and R^(L) is a moiety having theformula

wherein: ring B is selected from the group consisting of isoxazoyl,oxadiazoyl, oxazolyl, phenyl, pyridinyl, pyrazinyl, pyrimidinyl, andpyrazolyl; p is 0 or more; and each R^(B) group (when present) isindependently selected from the group consisting of fluoro, chloro,bromo, —CN, —S(O)₂CH₃, —OCH₃, —O-cyclopropyl, —O—CH₂-cyclopropyl,—OCH₂—C≡C—H, —OCH₂—C≡C—CH₃, methyl, cyclopropyl, —CH₂-cyclopropyl,—CH₂OCH₃, —C≡C—CH₃, —CF₃, —CHF₂, —CH₂F, —OCF₃, —OCHF₂, —OCH₂F, and—OCH₂CH₂F.
 8. A compound of claim 1, or a tautomer thereof, or apharmaceutically acceptable salt of said compound or said tautomer, saidcompound selected from the group consisting of:


9. A pharmaceutical composition comprising a compound according to claim1, or a tautomer thereof, or a pharmaceutically acceptable salt of saidcompound or said tautomer, and a pharmaceutically acceptable carrier ordiluent.
 10. A method of treating a disease or pathology, wherein saiddisease or pathology is Alzheimer's disease, olfactory impairmentassociated with Alzheimer's disease, Down's syndrome, olfactoryimpairment associated with Down's syndrome, Parkinson's disease,olfactory impairment associated with Parkinson's disease, stroke,microgliosis brain inflammation, pre-senile dementia, senile dementia,progressive supranuclear palsy, cortical basal degeneration, β-amyloidangiopathy, cerebral amyloid angiopathy, hereditary cerebral hemorrhage,mild cognitive impairment, glaucoma, amyloidosis, type II diabetes,diabetes-associated amyloidogenesis, scrapie, bovine spongiformencephalitis, traumatic brain injury, or Creutzfeld-Jakob disease, saidmethod comprising administering a compound according to claim 1, or atautomer thereof, or a pharmaceutically acceptable salt of said compoundor said tautomer, to a patient in need thereof in an amount effective totreat said disease or pathology.
 11. The method of claim 10, whereindisease or pathology is Alzheimer's disease.